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Geriatr Gerontol Int 2015; 15: 521–534
REVIEW ARTICLE
Effect of pharmacological treatment for urinary incontinence in the elderly and frail elderly: A systematic review Eva Samuelsson,1 Jenny Odeberg,2 Karin Stenzelius,3 Ulla Molander,4 Margareta Hammarström,5 Karin Franzen,6 Gunnel Andersson6 and Patrik Midlöv7 1
Department of Public Health and Clinical Medicine, Umeå University, Umeå, 2Swedish Council on Health Technology Assessment (SBU), Department of Clinical Science and Education, Karolinska Institutet, Stockholm, 3Department of Care Science, Malmö University, 7Center for Primary Health Care Research, Lund University, Malmö, 4Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, and 6School of health and Medical Sciences, Örebro University, Örebro, Sweden 5
Aim: The prevalence and severity of urinary incontinence (UI) increase with age and comorbidity. The benefits of pharmacotherapy for UI in the elderly are questionable. The aim of the present study was to systematically review the efficacy of pharmacological treatment for UI in the elderly and frail elderly. Methods: We searched PubMed, EMBASE, Cochrane library and Cinahl databases through October 2013 to identify prospective controlled trials that evaluated pharmacological treatment for UI in persons aged ≥65 years. Elderly persons living in nursing homes were regarded as frail elderly. Outcomes were urinary leakage, quality of life and adverse events. Results: We screened 1038 abstracts and assessed 309 full-text articles. We identified 13 trials of high or moderate quality; 11 evaluated anticholinergic drugs and two evaluated duloxetine. Oxybutynin, the only drug studied in the frail elderly population, had no effect on urinary leakage or quality of life in elderly with urgency UI (UUI). Seven trials evaluated the effects of darifenacin, fesoterodine, solifenacin, tolterodine or trospium. Urinary leakage decreased (standard mean difference: −0.24, 95% confidence interval −0.32–0.15), corresponding to a reduction of half a leakage per 24 h. Common side-effects of treatment were dry mouth and constipation. Data were insufficient for evaluation of the effect on quality of life or cognition. The evidence was insufficient to evaluate the effects of duloxetine. No eligible studies on mirabegron and estrogen were found. Conclusions: Anticholinergics have a small, but significant, effect on urinary leakage in older adults with UUI. Treatment with drugs for UUI in the frail elderly is not evidence based. Geriatr Gerontol Int 2015; 15: 521–534. Keywords: elderly, frail elderly, pharmacotherapy, systematic review, urinary incontinence.
Introduction Urinary incontinence (UI) is a common problem for people worldwide, and the World Health Organization (WHO) defines urinary incontinence as one of the “four giants” of geriatrics.1,2 Its prevalence and severity increase with age and comorbidity.1,3,4 UI can severely affect quality of life, and its costs for society are high.1,5
Accepted for publication 14 November 2014. Correspondence: Dr Eva Samuelsson MD PhD, Department of Public Health and Clinical Medicine, Umeå University, Hus 10, plan 5, Östersunds Hospital, Kyrkgatan 16, S-831 83 Östersund, Sweden. Email: [email protected]
© 2015 Japan Geriatrics Society
Urgency urinary incontinence (UUI) is characterized by leakage that is accompanied by or immediately preceeded by urgency, whereas stress urinary incontinence (SUI) is characterized by leakage on effort or exertion or on sneezing or coughing.6 Mixed urinary incontinence (MUI) is a combination of both. The mean prevalence of UUI and/or MUI is estimated to be 8–30% in ages ≥65 years, and is more prevalent in women than in men.1 SUI affects approximately 10–12% of the women in this age group.3 Changes in the bladder, in the prostate and/or in the pelvic floor contribute to an increase in UI, whereas comorbid conditions affecting the neurological control of the bladder and polypharmacy are other important factors explaining the increase in prevalence by age. The doi: 10.1111/ggi.12451
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type of UI is diagnosed based on a patient’s history and bladder diary. A physical examination, a urinary sample for detection of hematuria or bacteriuria, measurement of the residual urine volume, and general assessment of comorbidity, cognition and frailty are especially important in the aged patient.6,7 Because of the multifactorial causes of UI and the susceptibility of the elderly to adverse drug events, treatment of UI must be individualized. Lifestyle changes, such as weight loss for the obese and reduced intake of caffeinated drinks or other fluids (if intake is high), have shown beneficial effects in the treatment of UI.6–8 However, these effects have not been shown in the elderly population. A systematic review of care intervention studies for UI in care homes showed that combined physical and behavioral therapy yielded short-term improvements. However, there are few studies of long-term effectiveness and more complex behavioral interventions.9
Treatment of urgency urinary incontinence The recommended basic treatment, based on experience and research in younger people, is bladder training or scheduled voiding and pelvic floor muscle training in women.6,7 Anticholinergic drugs are often the next option.7 Many different anticholinergic drugs have been introduced for treatment of overactive bladder (OAB), a symptom triad defined as “urgency, with or without urgency urinary incontinence, usually with frequency and nocturia.”6 Approximately one-third to one-half of people with OAB also have incontinence.10,11 The available anticholinergic drugs for UUI are oxybutynin, tolterodine, fesoterodine, solifenacin, darifenacin and trospium. Mirabegron, a selective β3-adrenoceptor agonist, is also licensed for treatment of UUI. The persistence rates for anticholinergic drugs are poor; just 12–39% of patients continue to take medication for UUI after 1 year.12 Compliance is also low; the medication dispensed covers approximately one-third of the number of days between two prescriptions of the drug.12 Persistence and compliance seem to worsen with older age.12 Frequently reported reasons for discontinuation are lack of effect, improvements without medication, switching to other medication and side-effects.13 A recent systematic review of anticholinergic drugs for UI in women concluded that drug treatment resulted in a small, but clinically important, improvement in UI compared with placebo, with a similar effectiveness for all drugs.14 Published articles reported common and expected adverse events, and the authors suspected selective harms reporting when they compared data from the published articles with data from clinical trials.gov.14 Only a few studies regarding elderly and frail elderly women have been published, and the safety of 522 |
drugs in the presence of comorbidities and concomitant medications remains to be clarified.14
Treatment of stress urinary incontinence Pelvic floor muscle training is recommended as a basic treatment for SUI.7,15 A second option is surgery using a synthetic mesh supporting the bladder neck at constraint. However, studies on surgery in elderly women are lacking.16 Pharmacological treatment might be a third possibility for the treatment of SUI. Duloxetine, a serotonin–norepinephrine reuptake inhibitor, is approved for the treatment of SUI in many countries. Oral estrogen is not indicated for the treatment of UI. The findings on the effectiveness of topical estrogen for the treatment of UI are conflicting, although they are often used in older women.7,14,17 The benefits of pharmacotherapy to treat UI in the elderly have been questioned, as has the risk of adverse effects. Therefore, the aim of the present systematic review was to evaluate the effects of pharmacotherapy for urinary incontinence in elderly and frail elderly populations.
Methods Type of studies Within the Swedish Council on Technology Assessment in Health Care, we carried out a systematic review of randomized controlled trials and prospective controlled observational studies that evaluated interventions for drug treatment of urinary incontinence in the elderly and frail elderly population. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations for systematic reviews.18
Search strategy Search strategies are listed and provided as Supporting Information (Appendix S1), and the PubMed (NLM), EMBASE (Elsevier), Cochrane Library (Wiley) and Cinahl (EBSCO) databases were searched up to 3 October 2013. Additionally, reference lists, books and websites were used to identify further studies.
Assessment for quality and relevance Two reviewers (PM and ES), with clinical and research expertise, independently screened abstracts and titles using standard eligibility criteria. Full-text articles were retrieved if either or both of the reviewers considered a study potentially eligible. Both reviewers read the fulltext articles, and a consensus was achieved for eligibility. © 2015 Japan Geriatrics Society
Pharmacotherapy of geriatric incontinence
A list of the excluded articles is provided as Supporting Information (Appendix S2). Each eligible study was assessed for methodological quality and relevance by the two reviewers independently, using checklists and a structured review protocol that is standard practice at the Swedish Council on Technology Assessment in Health Care. Contact with the author was made in one case to ascertain that data in two different articles were not from the same study.19,20 No other contact was made with authors. The risk of bias for each study was assessed using structured protocols. Studies were scored into low, moderate or high risk of bias (Fig. 1). The results of the scoring were discussed among and agreed on by all authors. Studies with moderate or low risk of bias were included in the further analyses and meta-analysis.
Data synthesis Data synthesis was carried out, when possible, using Review Manager (RevMan, version 5.1; The Nordic Cochrane Centre, Copenhagen, Denmark), and using inverse variance and the random effects model. This model was used due to clinical heterogeneity. For dichotomous outcomes, we estimated the risk difference (RD) and the 95% confidence interval (CI); for continues outcomes, we estimated the mean difference (MD) or standard mean difference (SMD) and the 95% CI. Extracted data from the included studies are summarized in evidence tables. In one of the trials, important outcome data on urinary leakage was manually estimated from graphs.21 In three studies, data on urinary leakage were reported
Risk of study bias Risk of bias is assessed by the extent to which the outcome of an individual study is sensitive to methodological weaknesses. SBU uses only studies with low or moderate risk of bias in the assessment of quality of evidence. Quality of evidence SBU uses GRADE, an international evidence grading system. Study design is the primary factor considered in the overall appraisal, which is performed for each outcome of interest. The quality of evidence is rated down if one or several limitations are present: study limitations, inconsistency of results, imprecision of the estimated result, indirectness of evidence and risk of publication bias. For observational studies, quality of evidence may be rated up if there is a strong effect or a dose-response relationship. The quality of evidence has four levels: High quality of evidence (⊕⊕⊕⊕) Based on studies with low or moderate risk of bias with no factors that weaken the overall assessment. Moderate quality of evidence (⊕⊕⊕) Based on studies with low or moderate risk of bias with a single factor that weakens the overall assessment. Low quality of evidence (⊕⊕) Based on studies with low or moderate risk of bias with some factors that weaken the overall assessment. Very low quality of evidence (⊕) When the quality of evidence is very low, SBU considers that it is, in practice, insufficient. Very low quality of evidence could be due to weaknesses on several areas or that all of the studies have high bias risks.
Figure 1 Quality of evidence. GRADE, Grading of Recommendations Assessment, Development and Evaluation; SBU, Swedish Council on Technology Assessment in Health Care. © 2015 Japan Geriatrics Society
The stronger the quality of evidence, the lower the likelihood that new research findings would affect the documented results within the foreseeable future. Conclusions SBU’s conclusions are based on an overall assessment of benefits, risks, ethical considerations, and cost effectiveness.
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as median percentage change or Hodges–Lehmann difference, thus rendering analysis in RevMan impossible.22–24 The conclusions were based on a synthesis of the research evidence, using the Grading of Recommendations Assessment, Development and Evaluation approach.25,26
Study eligibility All randomized controlled trials and prospective controlled observational studies of pharmacological treatment for urinary incontinence in the elderly population were included in the present systematic review. Studies on OAB were included if baseline data and outcomes for patients with urinary leakage were reported separately. No time limits were imposed regarding date of publication; however, outdated treatments were excluded. Eligible outcomes were episodes of incontinence/urinary leakage, quality of life and adverse events. We had no limit on the duration of treatment or follow-up time. Only studies written in English were included. In the present systematic review, older persons living in long-term care institutions were regarded as frail elderly. We did not find any studies on communitydwelling frail elderly. Inclusion criteria for the studies in the present systematic review: Patients • Patients aged 65 years or older with urinary incontinence (elderly) • Patients living in nursing homes (frail elderly) • At least 20 patients in the intervention group and 20 in the control group. Intervention • Treatment with one or more drugs for urinary incontinence • The study design should be a randomized controlled study or observational cohort study. Control • Treatment with placebo or other specified treatment. Outcomes • Urinary leakage, quality of life or adverse events.
Results All studies that met the inclusion criteria for the present review were randomized, placebo-controlled studies. A total of 13 studies of moderate or high quality were included, just three of which had a population of frail elderly. The characteristics and outcomes of the included studies are presented in Table 1. For UUI, we included studies for oxybutynin,23,27–29 tolterodine,30 fesoterodine,21 solifenacin,31,32 darifenacin22,24 and trospium.33 Two studies on duloxetine for SUI were also included.19,20 524 |
There were no publications on estrogen or mirabegron that fulfilled the inclusion criteria. The flow chart for inclusion of studies is presented in Figure 2.
Urgency urinary incontinence Frail elderly Three of the included publications described the effect of oxybutynin in frail elderly patients with urinary incontinence.27–29 Two of these publications were from the same study.28,29 In these two studies, the effect of oxybutynin versus placebo was evaluated in nursing home residents in the USA and included 200 participants. The results of these studies showed no effect of oxybutynin on urinary leakage in frail elderly patients, and they did not find any differences in adverse effects between the oxybutynin and placebo groups.
Elderly Eight studies evaluated the effect of anticholinergic drugs on urinary incontinence in elderly patients (not frail). The studies included 3253 patients from Asia, Australia, Europe, North and South America, and South Africa. The effects of the different drugs on urinary leakage and quality of life are presented in Table 2. The number of urinary leakages decreased for all drugs, except for oxybutynin. The absolute decrease corresponded to approximately half a leakage per 24 h, from a baseline frequency of approximately three leakages per 24 h. Three of the studies included validated assessments of health-specific quality of life; two of them used the OAB questionnaire,21,24 and one used the Kings Health Questionnaire.33 In the studies in which fesoterodine21 and darifenacin24 were evaluated, the OAB questionnaire improved significantly, but no significant improvement in Kings Health Questionnaire was shown when trospium was studied.33 The metaanalysis of the effect of anticholinergic drugs versus placebo is shown in Figure 3. Overall, a significant effect on the frequency of urinary leakage was found. Adverse effects were more frequent in the treatment groups. There was a similar pattern of adverse effects in studies of anticholinergics, except for oxybutynin. Dry mouth affected 11–32% of patients taking anticholinergics, compared with 0–8% in the placebo group. Corresponding percentages for constipation were 6–24% in the group taking the active drug and 0–8% in the placebo group. None of the studies included any specific assessments of cognition (Table 3). The overall assessment of the effects of treatment and the quality of evidence are presented in Table 4.
SUI Two studies evaluating the effect of duloxetine on SUI were included; there were a total of 500 participants © 2015 Japan Geriatrics Society
1.9 UUIE/24 h
No. IE/week: 18.3–21
>65 years with ≥1 UUI episode per 24 h 65–74 years, mean age 69.2 years ≥75 years, mean age 78.6 78% women
>65 years with OAB, at least 1 UUIE/24 h, capable of visiting a toilet unaided. Mean age: 71.6 years (range 65–88) 77.6% women
DuBeau et al. 201221 USA, Central and South America, Europe, Asia, South Africa.
Foote et al. 200522 Multicenter study >4 different countries
Severity of UI at baseline
Approximately 20 UUIE/week
Population Mean age Criteria for UI
Age ≥65 years, >1 UUIE/day Independent toileting. 77.4% women Mean age: 72 ± 5 years
Anticholinergic Chapple et al. 200724 USA, Poland, South Africa, Hungary, Sweden, UK, Germany
Study and country
© 2015 Japan Geriatrics Society Darifenacin 7.5 or 15 mg once daily 12 weeks I = 207 (no data) C = 110 (2)
Fesoterodine 4 mg daily 1 week, 8 mg daily 11 weeks 12 weeks I (65–74 years) = 379 (27) I (> 75 year) = 167 (11) C (65–74 years) = 199 (7) C (> 75 years = 107 (11)
Darifenacin 7.5 mg daily, voluntary up-titration to 15 mg after 2 weeks 12 weeks I = 266 (22) C = 133 (16)
Intervention and control n (dropouts)
Urinary leakage (12 weeks) UUIE/week: I, 19.8–14.0; C, 21.0–13.0; NS diff HLD = −1 (−2.83, 1) Responder rates ≥50% reduction from baseline in UUIE: I, 186 (70%); C, 77 (58%); RD = 0.12 (0.02, 0.22)* Quality of life (OABq) Week 6, mean change: I, 20.9; C, 15.3; P < 0.001; MD = 5.60 (2.27, 8.93)* Week 12, mean change: I, 22.9; C, 16.8; P < 0.001; MD = 6.10 (2.47, 9.73) Adverse effects (12 weeks) AAE: I, 149 (56.0%); C, 60 (45.1%); RD = 0.11 (0.01, 0.21)* Dry mouth: I, 59 (22.2%); C, 5 (3.8%); RD = 0.18 (0.12, 0.24)* Constipation: I, 41 (15.4%); C, 11 (8.3%); RD = 0.07 (0.01, 0.14)* Urinary leakage Difference vs placebo after 12 weeks 65–74 years, approx 1.9–1.6 UUIE/24 h, P = 0.0307 >75 years, approx 1.8–1.25 UUIE/24 h, P = 0.0594 Quality of life (OABq) HRQL (OABq) significant effect in both age groups (P = 0.0028 65–74 years, P = 0.0033 > 75 years) Adverse effects (12 weeks) Dry mouth: 65 − 74 years, 31.9% vs 6.0%; >75 years, 29.9% vs 5.6% Constipation: 65–74 years, 5.8% vs 2.5%; >75 years, 9.6% vs 1.9% Cognition: No cognitive adverse events >1% were reported in any group, no specific assessment of cognition Urinary leakage IE/week, (median reduction, 12 weeks) BL: 7.5 mg, 21.0; 15 mg, 17.2; C, 18.3 12 weeks: 7.5 mg, −11.2; C, 4.8; 15 mg, −10.8; C, −6.8 7.5 mg WMD = −5.9 (−9.1, −2.2)*** 15 mg WMD = −4.1 (−6.4, −1.6*** Quality of life No information Adverse effects AAE: C, 56 (50.9%); 7.5 mg, n = 52 (53.6%); 15 mg, n = 76 (69.1%); 7.5 mg RD = 0.03 (−0.11, 0.16); 15 mg RD = 0.18 (0.05, 0.31)* Dry mouth: C, 5 (5%); 7.5 mg, 20 (21%); 15 mg, 23 (31%); 7.5 mg RD = 0.16 (0.07, 0.25)*; 15 mg RD = 0.26 (0.17, 0.36)* Constipation: C, 7 (6); 7.5 mg, 18(19%); 15 mg, 26 (24%); 7.5 mg RD = 0.12 (0.03, 0.21)*; 15 mg RD = 0.17 (0.08, 0.26)*
Outcomes (95% CI)
Table 1 Drugs for urinary incontinence in the elderly: summary of included studies (n = 13)
Moderate RCT Sub group analysis Sponsored by Pfizer, Novartis Pharma, Thomson Acumed.
Moderate Post-hoc analysis of subjects aged ≥65 years; pooled data from two RCT Sponsored by Pfizer
High RCT Masked random allocation, large number of patients, well described RCT, appropriate outcomes Sponsored by Novartis Pharmaceuticals
Quality of study Comments
Pharmacotherapy of geriatric incontinence
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526 | Trosphium chloride 60 mg ER once daily 12 weeks I = 85 (11) C = 58 (8)
Median UUIE/week: I: 22.17, C: 16.33
OAB > 6 months ≥3 episodes of UUI/3 days Age >75 years, Mean age: 79 years 73% women
Sand et al. 201133 USA
Oxybutynin 2.5–5 mg × 3 + prompted voiding 20 days Cross-over to placebo + prompted voiding I = 75 (12) C = 75 (12)
8.6 ± 3.4 IE/3 days
Nursing home residents with UUI, at least one “wet check” per day. Mean age: 85.6 ± 8.6 years Ability to say his/her name or reliably point one of two objects.
Ouslander et al. 199527 USA
Intervention and control n (dropouts) Oxybutynine 5 mg extended-release once daily during four weeks, placebo controlled I = 26 (1) C = 24 (2)
Female nursing home residents ≥65 years with UUI MMSE 5–23 Mean age: 88.6 ± 6.2 years
Lackner et al. 200828 Lackner et al. 201129 USA
Severity of UI at baseline 6.8–9 UIE/day
Population Mean age Criteria for UI
Study and country
Table 1 Continued
Urinary leakage UIE: No. wet hourly pad checks, 8 am to 4 pm two consecutive days, median (% change) BL: I, 6; C, 4.5 4 weeks: I, 2 (−38%); C, 2.5 (−53%), P = 0.97, MD = −8.07 (−37.84, 21.71) Quality of life No information Adverse effects CAM score change from baseline BL: I, 2.0; C, 1.8 Day 28: I, −0.6; C, −0.5 Treatment difference = 0.167 (−0.7, 1) Median change MMSE score: day 28, P = 0.98 Median change SIB score: day 28, P = 0.62 Agitation BARS score: No group differences in the mean BARS score change at any time-point (P = 0.50–0.94) Adverse events (4 weeks) AAE: I, 8(31%); C, 9 (38%); RD = −0.07 (−0.33, 0.20) Constipation: I, 2 (8%); C, 0; RD = 0.08 (−0.05, 0.20) Dry mouth: I, 1 (4%); C, 1 (4%); RD = −0.00 [−0.11, 0.11] Confusion: I, 0; C, 1 (4%); RD = −0.04 (−0.15, 0.06) Urinary leakage (day 20) No. IE/3 days BL: 8.6 Day 20: I, 6.8; C, 7.7; MD = −1.10 (−2.39, 0.19) Quality of life No information Adverse effects AAE: RD = 0.02 [−0.01, 0.05] Constipation: I, 16 (30%); C, 13 (25%); RD = 0.06 (−0.11, 0.23) Dry mouth: I, 22(42%); C, 19 (35%); RD = 0.07 (−0.11, 0.26) Urinary leakage (12 wk) Change in mean number of UUIE/wk: I, 22.17 (69.9% reduction); C, 16.33 (25% reduction); P = 0.04 Quality of life Only significant difference was in severity measures domain: I, −8.08 (SE 1.02); C, −5.63 (1.31); P = 0.03; OABq MD = −2.45 (−5.70, 0.80) Greater numerical increase in I vs C, P = 0.02 Adverse effects (12 weeks) Constipation: I, 9(10.6%); C, 0; RD = 0.11 (0.04, 0.18)* Dry mouth: I, 9 (10.6%); C, 2 (3.4%); RD = 0.07 (−0.01, 0.15)
Outcomes (95% CI)
Moderate RCT Subgroup analysis with pooled data from two studies. Results from the placebo-controlled part of the study are reported in this table. Study sponsored by Allergan, Inc and Endo Pharmaceuticals Inc.
Moderate RCT Very frail elderly Difficult to reliable ascertain side effects because of severe cognitive impairment.
Moderate RCT Few patients available for assessment of adverse effect on cognition Sponsored by research grant from Ortho-McNeil Pharmaceutical
Quality of study Comments
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I: 10 UIE daytime/week C: 7 UIE daytime/week
2.9 ± 0.2 UIE/24 h
23 UIE/week
Outpatients ≥70 years, symptoms of urinary frequency, urgency and urge incontinence. Mean age: 82 ± 6 years 95% women MMSE score: 28 ± 7.6
≥8 micturition/day and mean of ≥1 UI/day or mean of ≥1 UUIE/day Mean age: 71.9 years 74.5% women
>5UUIE/week, >8 micturitions/24 h Mean age: 74 ± 6 years 74.4% women
Szonyi et al. 199523 UK
Wagg et al. 200632 Cardozo et al. 200631 UK, USA, France
© 2015 Japan Geriatrics Society
Zinner et al. 200230 Europe, USA, Canada, Australia, and New Zealand Tolterodine ER capsules 4 mg once daily 12 weeks I = 214 (21) C = 223 (29)
Solifenacin 5 mg or 10 mg 12 weeks I (5 mg) = 192 (9) I (10 mg) = 431 (40) C = 422 (23)
Oxybutynin 2.5 mg twice daily and bladder training, placebo controlled 6 weeks I = 30 (8) C = 30 (5) Urinary leakage Micturition chart: C, 28; I, 24 Change in IE/day during first 14 days vs last 14 days Median change: −9.5 (−11, 3) I, 10–8 (difference 8); C, 7–7 (difference 7) Quality of life No information Complications/adverse effects (insufficient data, no. patients not given) Dry mouth: I, 93%; C, 86%; RD = 0.07 (−0.08, 0.22) Constipation: I, 50%; C, 45%; RD = 0.03 (−0.22, 0.29) Urinary leakage IE/day (mean change from baseline) Baseline; change after 12 weeks 5 mg: 2.5;-1.5 10 mg: 3.0;-1.9 C: 3.0;-1.0 5 mg MD = −0.63 (−1.12, −0.13)*; 10 mg MD = −0.86 (−1.19, −0.54)* Quality of life No information Adverse events (12 weeks) Dry mouth: 5 mg, 26 (13.5%); 10 mg, 136 (31.6%); C, 20 (4.7%); 5 mg RD = 0.09 (0.04, 0.14)*; 10 mg RD = 0.27 (0.22, 0.32)* Constipation): 5 mg, 18 (9.4%); 10 mg, 78 (18.1%); C, 18 (4.3%); 5 mg RD = 0.05 (0.01, 0.10)*; 10 mg RD = 0.14 (0.10, 0.18)* Urinary leakage (12 weeks) IE/week (mean reduction): I, 23.2–11.5; C, 23.4–6.3; MD = −5.20 (−8.33, −2.07)* Quality of life No information Complication/adverse effects (12 weeks) AAE: I, 116 (54.2%); C, 102 (46.0%), RD = 0.08 (−0.01, 0.18) Dry mouth: I, 52 (24.3%); C, 16 (7.2%); RD = 0.17 (0.10, 0.24)* Constipation: I, 13 (6.1%); C, 10 (4.5%); RD = 0.02 (−0.03, 0.06)
High RCT Sponsored by Pharmacia
Moderate Retrospective analysis of pooled data from four studies Sponsored by Yamanouchi Pharmaceuticals
Moderate RCT Sponsored by Smith&Nephew Pharmaceuticals Ltd
Pharmacotherapy of geriatric incontinence
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Mean UIE/week at baseline I: 20.5, C: 21.6
Women ≥65 years with SUI ≥7 UIE/week Mean age not known
Severity of UI at baseline
Community-dwelling women, aged ≥65 years SUI or stress-dominant MUI. ≥7 UIE/week. MMSE > 80) Mean age: 71 years No cognitive impairment: 79.25%
Population Mean age Criteria for UI
Duloxetin 40 mg twice daily 12 weeks I = 111 (no information of drop-outs for age group >65 years, 28% dropout for the whole group). C = 124 (no information)
Duloxetine 20 mg twice daily 40 mg twice daily De-escalation/discontinuation phase. 2 + 10 + 4 weeks. I = 134 (22) C = 131 (17)
Intervention and control n (dropouts)
Urinary leakage Change in mean IEF/week (24-h diaries) 6 weeks: I, −11.7; C, −6.9 Absolute change: MD = −4.80 (−7.66, −1.94)* IEF responder rate (reduction ≥50%): I, 72(57%); C, 43 (35%); P < 0.001 CS; RD = 0.22 (0.10, 0.34)* Quality of life (16 weeks) I-QOL, mean change, total score: I, 12.81; C, 6.84; MD = 5.97 (2.41, 9.53)*; P < 0.001 Responder rate I-QOL, percentage of patients with increase in I-QOL total score of ≥6.3: I, 69 (55%); C, 59 (48%); RD = 0.06 (−0.06, 0.19) Adverse effects (16 weeks) Dry mouth: I, 26 (19.4%), C, 2 (1.5%); RD = 0.18 (0.11, 0.25)* Constipation: I, 14 (10.4%), C, 1 (0.8%); RD = 0.10 (0.04, 0.15)* Urinary leakage IEF/week Median change (%): I, −43.75; C, −22.95; P = 0.052 Quality of life I-QOL, mean change (12 weeks): I, 61.4 + 9.4; C, 59.6 + 5.8; P = 0.043; MD = 3.54 (−0.34, 7.42) Adverse effects Adverse effects were not significantly different in women of different ages, but there was no specific information on adverse events for the age group >65 years
Outcomes (95% CI)
Moderate RCT Small absolute effects, clinical relevance. Post-hoc analysis of subgroup ≥65 years from four controlled trials. Higher dropout rate for the intervention vs control group for all ages. Both authors are fully employed by Eli Lilly and Company and hold stock and stock options in the company
High RCT, masked random allocation, blinded, adequate outcome variables described with absolute and relative data Sponsored by Eli-Lilly and Boehringer Ingelheim
Quality of study Comments
*P < 0.05, ***P < 0.001. AAE, any adverse effects; AD, ANCOVA difference; AE, adverse effects; AMD, adjusted mean difference; BARS, Brief Agitation Rating Scale; BL, baseline; BT, bladder training; C, control; CAM, confusion assessment method; CS, clinical sign; F/M, female/male; GDS, Global Deterioration Scale; HLD, Hodges–Lehmann difference; HRQL, health related quality of life; I, intervention; IE, incontinence episodes; IEF, incontinence episode frequency; I-QOL, Incontinence quality of life; MD, mean difference; MMSE, mini-mental state examination; MMSS, mini-mental state score; MUI, mixed urinary incontinence; NH, nursing home; NS, non-significant; OAB, over active bladder; OABq, overactive bladder questionnaire; PFMT, pelvic floor muscle training; PV, prompted voiding; PVR, post-void residual urinary volume; PVR, post-void residual volume; QOL, quality of life; RCT, randomized controlled trial; RD, risk difference; SE, Standard error; SIB, Severe Impairment Battery; SUI, stress urinary incontinence; UF, urinary frequency; UI, urinary incontinence; UIE, urinary incontinence episodes; UTI, urinary tract infection; UUI, urgency urinary incontinence; UUIE, urgency urinary incontinence episodes; WMD, Wilcoxon rank-sum test median difference.
Viktrup and Yalcin 200720 Africa, Australia, Europe, North America and South America
Duloxetine Schagen van Leeuwen et al. 200819 Germany, France, Netherlands, Spain, Sweden, Switzerland, South Africa
Study and country
Table 1 Continued
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Figure 2 studies.
Flowchart of included
from Australia, Africa, Europe, and North and South America.19,20 Schagen van Leeuwen et al. studied patients with UI, but just 40% of the included women had SUI, 7% UUI and the rest had MUI.19 There was a significant decrease in the number of urinary leakages in the treatment group compared with placebo (duloxetine: −11.7 urinary leakage episodes per week compared with placebo: −6.9, P = 0.0010). However, when only patients with SUI were analyzed, no effect on urinary leakage was found. Viktrup et al. showed no effects on the number of urinary leakages (duloxetine: −6.6 urinary leakage episodes per week compared with placebo: −3.6, P = 0.052). In the study by Schagen van Leeuwen et al., adverse effects (i.e. dry mouth, fatigue, constipation and hyperhidrosis) were more frequent in the treatment group. There were no data on adverse effects reported separately for the elderly in the study by Viktrup et al. In both studies, however, there was an improvement in quality of life (measured by I-QOL-score) in the treatment group, but the clinical significance of this small difference is unclear (Table 1).
Risk of bias in the included studies All 13 studies were placebo-controlled, and randomization was carried out on an individual basis. Although they all stipulated that the allocation procedure was © 2015 Japan Geriatrics Society
correct, it was not described in detail in all studies. Five studies did not report whether assessors were blinded to the treatment status of the participants and one of them contained no information of blinding at all. 20,21,31–33 The number of dropouts was generally small or moderate without any important difference between groups. However, of the six studies based on post-hoc data from the elderly, just two had complete information on dropouts and withdrawals.20–22,31–33 The compliance to treatment was acceptable where it was reported.22–24,28–30 Compliance varied between 80–100% of participants taking more than 75% of prescribed doses. Pharmaceutical companies sponsored all of the studies but one.27
Discussion In the present systematic review, we found that treatment with anticholinergic drugs decreased the number of urinary leakages in elderly patients with UI. The effect in absolute numbers of urinary leakages is small – corresponding to half a leakage per 24 h. For anticholinergic drugs, adverse events such as dry mouth and constipation were more frequent compared with placebo. The effect of treatment with anticholinergics on quality of life remains unclear in elderly patients. Furthermore, there were no positive effects of | 529
530 | 887 (2 RCT)
852 65–74 years: 578 > = 75 years: 274 (1 RCT) 57 (1 RCT) 689 (1 RCT, 2 publications)
437 (1 RCT) 139 (1 RCT)
Darifenacin (Foote et al. 200522; Chapple et al. 200724)
Fesoterodine† (DuBeau et al. 201221)
Tolterodine (Zinner et al. 200230) Trospium (Sand et al. 201133)
23 per week 16.3–22.1 UIE/week
8 UI daytime/week 2.9 ± 0.2 UIE/24 h
17.2–21 UIE/week Not presented in Chapple 17 UI/week
Incontinence episode frequency at baseline
NS 5 mg solifenacin: 0.5 UI/24 h* 10 mg solifenacin: 0.9 UI/24 h* 0.7/24 h* 1.2/24 h*
Foote: 0.7/24 h* Not presented in Chapple 65–74 years: 0.3/24 h* ≥75 years: NS
Absolute decrease in number of incontinence episodes (treatment – placebo)
No data No significant improvement KHQ
No data No data
OABq significant improvement in 65–74 years, as well as ≥75 years
OABq significant improvement
Quality of life
*P < 0.05. †In this study, fesoterodine is compared with placebo and with tolterodine. As tolterodine is not compared with placebo, only participants on fesoterodine or placebo are included here. KHQ, Kings Health Questionnaire; OABq, overactive bladder questionnaire; RCT, randomized controlled trial; UIE, urinary incontinence episodes.
Oxybutynine (Szonyi et al. 199523) Solifenacin (Cardozo et al. 200631; Wagg et al. 200632)
No. patients (no. studies and study design)
Drug
Table 2 Effects of anticholinergic drugs in elderly (not frail elderly) with urgency urinary incontinence; urinary leakage and quality of life
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Figure 3
Improvement in number of urinary leakages in the elderly; anticholinergic drugs versus placebo.
anticholinergics on UI in frail elderly in the two studies that were included. The evidence is insufficient to evaluate the effects of duloxetine on SUI in the elderly. Just two studies on SUI fulfilled our inclusion criteria, and neither of them showed that duloxetine had an effect on the number of urinary leakages in patients with SUI. There were no studies that compared a standard-of-care group (i.e. pelvic floor muscle training). Different kinds of measurements for quality of life, adverse effects and symptoms of UI make it difficult to compare the results of different studies. Furthermore, results regarding adverse effects might not be applicable for the general population of the elderly. Not all studies reported whether the participants had been treated with anticholinergic treatment for UUI before entering the study or not; if the participants had previous treatment, it could indicate a selection of participants that already tolerate the drugs. In the present systematic review, studies on adverse effects were not included unless results were reported separately for OAB patients with incontinence. However, there might be other studies on adverse effects of anticholinergics in OAB patients. Limitations of our review include the low number of studies on frail elderly individuals that we included and © 2015 Japan Geriatrics Society
the pragmatic definition of frailty (i.e. “nursing home residents”) that we used. There are two common definitions of physical frailty. According to Fried et al., frailty includes three or more of five symptoms: unintentional weight loss, exhaustion, weakness, slow walking speed and low physical activity.34 The other definition is based on the Frailty Index, where the number of impairments and conditions of the individual are added to create an index.35 Frailty is a state with increased vulnerability to stressors, and it is associated with increased mortality, especially in women.36,37 Frail individuals are therefore seldom included in drug trials. None of the studies we found on elderly individuals living in their own homes included an assessment of frailty. The present review on pharmacotherapy for urinary incontinence in frail elderly individuals was therefore limited to the few studies in which nursing home residents were assessed. In the elderly, and especially the frail elderly, the effect of medications on cognition is of great importance. It is well settled that anticholinergic drugs can have adverse effects on cognition in the elderly, but it has not yet been convincingly shown that discontinuation is associated with an increase in cognitive performance.38,39 There was a lack of adequate assessment of cognition in | 531
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Table 3 Adverse effects in elderly with urgency urinary incontinence treated with anticholinergics Drug
No. patients Dry mouth (no. studies and study design)
Darifenacin (Foote et al. 200522; Chapple et al. 200724) Fesoterodine† (DuBeau et al. 201221)
887 (2 RCT)
31% vs 5%* 24% vs 6%* 22.2 vs 3.8%* 15.4% vs 8.3%* RD = 0.20 (0.14, 0.25)* RD = 0.11 (0.06, 0.17)
852 (1 RCT)
65–74 years: 31.9% vs 6.0% ≥75 years: 29.9% vs 5.6%
Oxybutynine (Szonyi et al. 199523)
57 (1 RCT)
Solifenacin (Cardozo et al. 200631; Wagg et al. 200632) Tolterodine (Zinner et al. 200230)
689 (1 RCT, 2 publications) 437 (1RCT)
Trospium (Sand et al. 139 (1 RCT) 201133)
Constipation
Cognition
No data
65–74 years: 5.8% vs No cognitive adverse 2.5% events reported in any group, but no ≥75 years: 9.6% vs 1.9% specific assessment of cognition 93% vs 86% 50% vs 45% No data RD = 0.07 (−0.08, 0.22) RD = 0.03 (−0.22, 0.29) NS NS 31.6% vs 4.7%* 18.1% vs 4.3%* No data RD = 0.27 (0.22, 0.32) RD = 0.14 (0.10, 0.18) 24.3% vs 7.2%* RD = 0.17 (0.10, 0.24)
6.1% vs 4.5% RD = 0.02 (−0.03, 0.06) NS 10.6% vs 3.4% 10.6% vs 0%* RD = 0.07 (−0.01, 0.15) RD = 0.11 (0.04, 0.18) NS
No data
No data
*P < 0.05. †No P-value presented. RCT, randomized controlled trial.
Table 4 Overall assessment of the effects of treatment with anticholinergics drugs in the elderly with urgency urinary incontinence Effects
No. patients, studies and design
Overall assessment
Quality of evidence
Urinary leakage
2894 (7 RCT)
⊕⊕⊕
Quality of life
1375 (3 RCT)
Dry mouth Constipation Cognition
2960 (7 RCT) 2960 (7 RCT) No studies with assessment of cognition
No. UIE decrease with approximately half a leakage per 24 h Conflicting results; three studies with data on QOL, improvement in two of them 11–32% compared with 3–7% in placebo group 6–24% compared with 0–8% in placebo group Not possible to assess. Lack of studies.
⊕ ⊕⊕⊕ ⊕⊕⊕ ⊕
QOL, quality of life.
the included studies. One reason might be that there is no consensus of how to assess cognitive impairment.40 The follow-up period in the included studies was usually 12 weeks. Thus, the long-term effects of these anticholinergic drugs on UI have not been evaluated at all. An increase in mortality has previously been shown for long-term exposure of anticholinergic drugs.41 For mirabegron and estrogen, there were no studies that fulfilled our inclusion criteria. Estrogen is often 532 |
used in older women with UI, but the evidence supporting this use is scarce. Mirabegron is a relatively new drug, and there are no studies in the elderly, yet. Future studies are warranted to evaluate the effects and adverse effects of drugs on UI in the elderly, and especially in the frail elderly. Standardization of measurements for quality of life, adverse events and symptoms of UI would also greatly benefit this field of research. There is also a need for long-term studies, as © 2015 Japan Geriatrics Society
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well as studies that compare the effects of pharmacological treatment with the effects of nonpharmacological treatment.
Conclusion Anticholinergic drugs have a small, but significant, effect on urinary leakage in the elderly with urgency urinary incontinence. Adverse effects, such as dry mouth and constipation, were common, but none of the studies included a thorough assessment of cognition. Treatment with anticholinergics for UUI in the frail elderly is not evidence based. Further studies are required to evaluate the effects of duloxetine, mirabegron and estrogen in the elderly population.
Acknowledgments This study was financially supported by the Swedish Council on Technology Assessment in Health Care. We are grateful to Elisabeth Gustafsson for help with administration of the project.
Disclosure statements No potential conflicts of interest were disclosed.
References 1 Milsom I, Coyne KS, Nicholson S, Kvasz M, Chen CI, Wein AJ. Global prevalence and economic burden of urgency urinary incontinence: a systematic review. Eur Urol 2014; 65: 79–95. 2 WHO. Ageing and life course. [Cited 27 Jun 2014.] Available from URL: http://www.who.int/ageing/projects/ age_friendly_standards/en/ 3 Hannestad YS, Rortveit G, Sandvik H, Hunskaar S. A community-based epidemiological survey of female urinary incontinence: the Norwegian EPINCONT study. Epidemiology of Incontinence in the County of NordTrondelag. J Clin Epidemiol 2000; 53: 1150–1157. 4 Stenzelius K, Mattiasson A, Hallberg IR, Westergren A. Symptoms of urinary and faecal incontinence among men and women 75+ in relations to health complaints and quality of life. Neurourol Urodyn 2004; 23: 211–222. 5 Samuelsson E, Mansson L, Milsom I. Incontinence aids in Sweden: users and costs. BJU Int 2001; 88: 893–898. 6 Abrams P, Andersson KE, Birder L et al. Fourth International Consultation on Incontinence Recommendations of the International Scientific Committee: evaluation and treatment of urinary incontinence, pelvic organ prolapse, and fecal incontinence. Neurourol Urodyn 2010; 29: 213– 240. 7 National Institute for Health and Care Excellence. Urinary incontinence in women: the management of urinary incontinence in women. (Clinical Guideline 171) 2013: http://guidance.nice.org.uk/CG171 © 2015 Japan Geriatrics Society
8 Swithinbank L, Hashim H, Abrams P. The effect of fluid intake on urinary symptoms in women. J Urol 2005; 174: 187–189. 9 Flanagan L, Roe B, Jack B. Systematic review of care intervention studies for the management of incontinence and promotion of continence in older people in care homes with urinary incontinence as the primary focus (1966– 2010). Geriatr Gerontol Int 2012; 12: 600–611. 10 Milsom I, Abrams P, Cardozo L. How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int 2001; 87: 760–766. 11 Hartmann KE, McPheeters ML, Biller DH. Treatment of overactive bladder in women. Evid Rep Technol Assess (Full Rep) 2009; 187: 1–120. 12 Veenboer PW, Bosch JL. Long-term adherence to antimuscarinic therapy in everyday practice: a systematic review. J Urol 2014; 191: 1003–1008. 13 Benner JS, Nichol MB, Rovner ES et al. Patient-reported reasons for discontinuing overactive bladder medication. BJU Int 2010; 105: 1276–1282. 14 Shamliyan T, Wyman JF, Ramakrishnan R, Sainfort F, Kane RL. Benefits and harms of pharmacologic treatment for urinary incontinence in women: a systematic review. Ann Intern Med 2012; 156: 861–874, W301-10. 15 Shamliyan T, Wyman J, Kane RL. Nonsurgical Treatments for Urinary Incontinence in Adult Women: Diagnosis and Comparative Effectiveness. Comparative Effectiveness Review No. 36. Rockville, MD: University of Minnesota Evidence-based Practice Center, 2012. 16 Ogah J, Cody JD, Rogerson L. Minimally invasive synthetic suburethral sling operations for stress urinary incontinence in women. Cochrane Database Syst Rev 2009; (4)CD006375. 17 Cody JD, Jacobs ML, Richardson K, Moehrer B, Hextall A. Oestrogen therapy for urinary incontinence in postmenopausal women. Cochrane Database Syst Rev 2012; (10)CD001405. 18 Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and metaanalyses: the PRISMA statement. Int J Surg 2010; 8: 336– 341. 19 Schagen van Leeuwen JH, Lange RR, Jonasson AF, Chen WJ, Viktrup L. Efficacy and safety of duloxetine in elderly women with stress urinary incontinence or stresspredominant mixed urinary incontinence. Maturitas 2008; 60: 138–147. 20 Viktrup L, Yalcin I. Duloxetine treatment of stress urinary incontinence in women: effects of demographics, obesity, chronic lung disease, hypoestrogenism, diabetes mellitus, and depression on efficacy. Eur J Obstet Gynecol Reprod Biol 2007; 133: 105–113. 21 DuBeau CE, Morrow JD, Kraus SR, Creanga D, Bavendam T. Efficacy and tolerability of fesoterodine versus tolterodine in older and younger subjects with overactive bladder: a post hoc, pooled analysis from two placebocontrolled trials. Neurourol Urodyn 2012; 31: 1258–1265. 22 Foote J, Glavind K, Kralidis G, Wyndaele JJ. Treatment of overactive bladder in the older patient: pooled analysis of three phase III studies of darifenacin, an M3 selective receptor antagonist. Eur Urol 2005; 48: 471–477. 23 Szonyi G, Collas DM, Ding YY, Malone-Lee JG. Oxybutynin with bladder retraining for detrusor instability in elderly people: a randomized controlled trial. Age Ageing 1995; 24: 287–291. 24 Chapple C, DuBeau C, Ebinger U, Rekeda L, Viegas A. Darifenacin treatment of patients >or= 65 years with
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overactive bladder: results of a randomized, controlled, 12-week trial. Curr Med Res Opin 2007; 23: 2347–2358. Atkins D, Best D, Briss PA et al. Grading quality of evidence and strength of recommendations. BMJ 2004; 328: 1490. Guyatt GH, Oxman AD, Vist GE et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008; 336: 924–926. Ouslander JG, Schnelle JF, Uman G et al. Does oxybutynin add to the effectiveness of prompted voiding for urinary incontinence among nursing home residents? A placebocontrolled trial. J Am Geriatr Soc 1995; 43: 610–617. Lackner TE, Wyman JF, McCarthy TC, Monigold M, Davey C. Randomized, placebo-controlled trial of the cognitive effect, safety, and tolerability of oral extended-release oxybutynin in cognitively impaired nursing home residents with urge urinary incontinence. J Am Geriatr Soc 2008; 56: 862–870. Lackner TE, Wyman JF, McCarthy TC, Monigold M, Davey C. Efficacy of oral extended-release oxybutynin in cognitively impaired older nursing home residents with urge urinary incontinence: a randomized placebocontrolled trial. J Am Med Dir Assoc 2011; 12: 639–647. Zinner NR, Mattiasson A, Stanton SL. Efficacy, safety, and tolerability of extended-release once-daily tolterodine treatment for overactive bladder in older versus younger patients. J Am Geriatr Soc 2002; 50: 799–807. Cardozo L, Castro-Diaz D, Gittelman M, Ridder A, Huang M. Reductions in overactive bladder-related incontinence from pooled analysis of phase III trials evaluating treatment with solifenacin. Int Urogynecol J Pelvic Floor Dysfunct 2006; 17: 512–519. Wagg A, Wyndaele JJ, Sieber P. Efficacy and tolerability of solifenacin in elderly subjects with overactive bladder syndrome: a pooled analysis. Am J Geriatr Pharmacother 2006; 4: 14–24. Sand PK, Johnson Ii TM, Rovner ES, Ellsworth PI, Oefelein MG, Staskin DR. Trospium chloride once-daily
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extended release is efficacious and tolerated in elderly subjects (aged >/= 75 years) with overactive bladder syndrome. BJU Int 2011; 107: 612–620. Fried LP, Ferrucci L, Darer J et al. Untangling the concepts of disability, frailty and comorbidity: implications for improved targeting and care. J Gerontol A Biol Sci Med Sci 2004; 59: 255–263. Rockwood K, Mitnitsky A. Frailty defined by deficit accumulation and geriatric medicine defined by frailty. Clin Geriatr Med 2011; 27: 17–26. Clegg A, Young J, Iliffe S et al. Frailty in elderly people. Lancet 2013; 381: 752–762. Kulmala J, Nykänen I, Hartikainen S. Frailty as a predictor of all-cause mortality in older men and women. Geriatr Gerontol Int 2014; 14: 899–905. doi:10.1111/ggi.12190. Whalley LJ, Sharma S, Fox HC et al. Anticholinergic drugs in late life: adverse effects on cognition but not on progress to dementia. J Alzheimers Dis 2012; 30: 253–261. Salahudeen MS, Duffull SB, Nishtala PS. Impact of anticholinergic discontinuation on cognitive outcomes in older people: a systematic review. Drugs Aging 2014; 31: 185–192. Sink KM, Thomas J 3rd, Xu H, Craig B, Kritchevsky S, Sands LP. Dual use of bladder anticholinergics and cholinesterase inhibitors: long-term functional and cognitive outcomes. J Am Geriatr Soc 2008; 56: 847–853. Fox C, Richardson K, Maidment ID et al. Anticholinergic medication use and cognitive impairment in the older population: the medical research council cognitive function and ageing study. J Am Geriatr Soc 2011; 59: 1477– 1483.
Supporting information Appendix S1 Search strategies. Appendix S2 List of excluded articles.
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Geriatr Gerontol Int 2015; 15: 521–534
REVIEW ARTICLE
Effect of pharmacological treatment for urinary incontinence in the elderly and frail elderly: A systematic review Eva Samuelsson,1 Jenny Odeberg,2 Karin Stenzelius,3 Ulla Molander,4 Margareta Hammarström,5 Karin Franzen,6 Gunnel Andersson6 and Patrik Midlöv7 1
Department of Public Health and Clinical Medicine, Umeå University, Umeå, 2Swedish Council on Health Technology Assessment (SBU), Department of Clinical Science and Education, Karolinska Institutet, Stockholm, 3Department of Care Science, Malmö University, 7Center for Primary Health Care Research, Lund University, Malmö, 4Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, and 6School of health and Medical Sciences, Örebro University, Örebro, Sweden 5
Aim: The prevalence and severity of urinary incontinence (UI) increase with age and comorbidity. The benefits of pharmacotherapy for UI in the elderly are questionable. The aim of the present study was to systematically review the efficacy of pharmacological treatment for UI in the elderly and frail elderly. Methods: We searched PubMed, EMBASE, Cochrane library and Cinahl databases through October 2013 to identify prospective controlled trials that evaluated pharmacological treatment for UI in persons aged ≥65 years. Elderly persons living in nursing homes were regarded as frail elderly. Outcomes were urinary leakage, quality of life and adverse events. Results: We screened 1038 abstracts and assessed 309 full-text articles. We identified 13 trials of high or moderate quality; 11 evaluated anticholinergic drugs and two evaluated duloxetine. Oxybutynin, the only drug studied in the frail elderly population, had no effect on urinary leakage or quality of life in elderly with urgency UI (UUI). Seven trials evaluated the effects of darifenacin, fesoterodine, solifenacin, tolterodine or trospium. Urinary leakage decreased (standard mean difference: −0.24, 95% confidence interval −0.32–0.15), corresponding to a reduction of half a leakage per 24 h. Common side-effects of treatment were dry mouth and constipation. Data were insufficient for evaluation of the effect on quality of life or cognition. The evidence was insufficient to evaluate the effects of duloxetine. No eligible studies on mirabegron and estrogen were found. Conclusions: Anticholinergics have a small, but significant, effect on urinary leakage in older adults with UUI. Treatment with drugs for UUI in the frail elderly is not evidence based. Geriatr Gerontol Int 2015; 15: 521–534. Keywords: elderly, frail elderly, pharmacotherapy, systematic review, urinary incontinence.
Introduction Urinary incontinence (UI) is a common problem for people worldwide, and the World Health Organization (WHO) defines urinary incontinence as one of the “four giants” of geriatrics.1,2 Its prevalence and severity increase with age and comorbidity.1,3,4 UI can severely affect quality of life, and its costs for society are high.1,5
Accepted for publication 14 November 2014. Correspondence: Dr Eva Samuelsson MD PhD, Department of Public Health and Clinical Medicine, Umeå University, Hus 10, plan 5, Östersunds Hospital, Kyrkgatan 16, S-831 83 Östersund, Sweden. Email: [email protected]
© 2015 Japan Geriatrics Society
Urgency urinary incontinence (UUI) is characterized by leakage that is accompanied by or immediately preceeded by urgency, whereas stress urinary incontinence (SUI) is characterized by leakage on effort or exertion or on sneezing or coughing.6 Mixed urinary incontinence (MUI) is a combination of both. The mean prevalence of UUI and/or MUI is estimated to be 8–30% in ages ≥65 years, and is more prevalent in women than in men.1 SUI affects approximately 10–12% of the women in this age group.3 Changes in the bladder, in the prostate and/or in the pelvic floor contribute to an increase in UI, whereas comorbid conditions affecting the neurological control of the bladder and polypharmacy are other important factors explaining the increase in prevalence by age. The doi: 10.1111/ggi.12451
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type of UI is diagnosed based on a patient’s history and bladder diary. A physical examination, a urinary sample for detection of hematuria or bacteriuria, measurement of the residual urine volume, and general assessment of comorbidity, cognition and frailty are especially important in the aged patient.6,7 Because of the multifactorial causes of UI and the susceptibility of the elderly to adverse drug events, treatment of UI must be individualized. Lifestyle changes, such as weight loss for the obese and reduced intake of caffeinated drinks or other fluids (if intake is high), have shown beneficial effects in the treatment of UI.6–8 However, these effects have not been shown in the elderly population. A systematic review of care intervention studies for UI in care homes showed that combined physical and behavioral therapy yielded short-term improvements. However, there are few studies of long-term effectiveness and more complex behavioral interventions.9
Treatment of urgency urinary incontinence The recommended basic treatment, based on experience and research in younger people, is bladder training or scheduled voiding and pelvic floor muscle training in women.6,7 Anticholinergic drugs are often the next option.7 Many different anticholinergic drugs have been introduced for treatment of overactive bladder (OAB), a symptom triad defined as “urgency, with or without urgency urinary incontinence, usually with frequency and nocturia.”6 Approximately one-third to one-half of people with OAB also have incontinence.10,11 The available anticholinergic drugs for UUI are oxybutynin, tolterodine, fesoterodine, solifenacin, darifenacin and trospium. Mirabegron, a selective β3-adrenoceptor agonist, is also licensed for treatment of UUI. The persistence rates for anticholinergic drugs are poor; just 12–39% of patients continue to take medication for UUI after 1 year.12 Compliance is also low; the medication dispensed covers approximately one-third of the number of days between two prescriptions of the drug.12 Persistence and compliance seem to worsen with older age.12 Frequently reported reasons for discontinuation are lack of effect, improvements without medication, switching to other medication and side-effects.13 A recent systematic review of anticholinergic drugs for UI in women concluded that drug treatment resulted in a small, but clinically important, improvement in UI compared with placebo, with a similar effectiveness for all drugs.14 Published articles reported common and expected adverse events, and the authors suspected selective harms reporting when they compared data from the published articles with data from clinical trials.gov.14 Only a few studies regarding elderly and frail elderly women have been published, and the safety of 522 |
drugs in the presence of comorbidities and concomitant medications remains to be clarified.14
Treatment of stress urinary incontinence Pelvic floor muscle training is recommended as a basic treatment for SUI.7,15 A second option is surgery using a synthetic mesh supporting the bladder neck at constraint. However, studies on surgery in elderly women are lacking.16 Pharmacological treatment might be a third possibility for the treatment of SUI. Duloxetine, a serotonin–norepinephrine reuptake inhibitor, is approved for the treatment of SUI in many countries. Oral estrogen is not indicated for the treatment of UI. The findings on the effectiveness of topical estrogen for the treatment of UI are conflicting, although they are often used in older women.7,14,17 The benefits of pharmacotherapy to treat UI in the elderly have been questioned, as has the risk of adverse effects. Therefore, the aim of the present systematic review was to evaluate the effects of pharmacotherapy for urinary incontinence in elderly and frail elderly populations.
Methods Type of studies Within the Swedish Council on Technology Assessment in Health Care, we carried out a systematic review of randomized controlled trials and prospective controlled observational studies that evaluated interventions for drug treatment of urinary incontinence in the elderly and frail elderly population. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations for systematic reviews.18
Search strategy Search strategies are listed and provided as Supporting Information (Appendix S1), and the PubMed (NLM), EMBASE (Elsevier), Cochrane Library (Wiley) and Cinahl (EBSCO) databases were searched up to 3 October 2013. Additionally, reference lists, books and websites were used to identify further studies.
Assessment for quality and relevance Two reviewers (PM and ES), with clinical and research expertise, independently screened abstracts and titles using standard eligibility criteria. Full-text articles were retrieved if either or both of the reviewers considered a study potentially eligible. Both reviewers read the fulltext articles, and a consensus was achieved for eligibility. © 2015 Japan Geriatrics Society
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A list of the excluded articles is provided as Supporting Information (Appendix S2). Each eligible study was assessed for methodological quality and relevance by the two reviewers independently, using checklists and a structured review protocol that is standard practice at the Swedish Council on Technology Assessment in Health Care. Contact with the author was made in one case to ascertain that data in two different articles were not from the same study.19,20 No other contact was made with authors. The risk of bias for each study was assessed using structured protocols. Studies were scored into low, moderate or high risk of bias (Fig. 1). The results of the scoring were discussed among and agreed on by all authors. Studies with moderate or low risk of bias were included in the further analyses and meta-analysis.
Data synthesis Data synthesis was carried out, when possible, using Review Manager (RevMan, version 5.1; The Nordic Cochrane Centre, Copenhagen, Denmark), and using inverse variance and the random effects model. This model was used due to clinical heterogeneity. For dichotomous outcomes, we estimated the risk difference (RD) and the 95% confidence interval (CI); for continues outcomes, we estimated the mean difference (MD) or standard mean difference (SMD) and the 95% CI. Extracted data from the included studies are summarized in evidence tables. In one of the trials, important outcome data on urinary leakage was manually estimated from graphs.21 In three studies, data on urinary leakage were reported
Risk of study bias Risk of bias is assessed by the extent to which the outcome of an individual study is sensitive to methodological weaknesses. SBU uses only studies with low or moderate risk of bias in the assessment of quality of evidence. Quality of evidence SBU uses GRADE, an international evidence grading system. Study design is the primary factor considered in the overall appraisal, which is performed for each outcome of interest. The quality of evidence is rated down if one or several limitations are present: study limitations, inconsistency of results, imprecision of the estimated result, indirectness of evidence and risk of publication bias. For observational studies, quality of evidence may be rated up if there is a strong effect or a dose-response relationship. The quality of evidence has four levels: High quality of evidence (⊕⊕⊕⊕) Based on studies with low or moderate risk of bias with no factors that weaken the overall assessment. Moderate quality of evidence (⊕⊕⊕) Based on studies with low or moderate risk of bias with a single factor that weakens the overall assessment. Low quality of evidence (⊕⊕) Based on studies with low or moderate risk of bias with some factors that weaken the overall assessment. Very low quality of evidence (⊕) When the quality of evidence is very low, SBU considers that it is, in practice, insufficient. Very low quality of evidence could be due to weaknesses on several areas or that all of the studies have high bias risks.
Figure 1 Quality of evidence. GRADE, Grading of Recommendations Assessment, Development and Evaluation; SBU, Swedish Council on Technology Assessment in Health Care. © 2015 Japan Geriatrics Society
The stronger the quality of evidence, the lower the likelihood that new research findings would affect the documented results within the foreseeable future. Conclusions SBU’s conclusions are based on an overall assessment of benefits, risks, ethical considerations, and cost effectiveness.
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as median percentage change or Hodges–Lehmann difference, thus rendering analysis in RevMan impossible.22–24 The conclusions were based on a synthesis of the research evidence, using the Grading of Recommendations Assessment, Development and Evaluation approach.25,26
Study eligibility All randomized controlled trials and prospective controlled observational studies of pharmacological treatment for urinary incontinence in the elderly population were included in the present systematic review. Studies on OAB were included if baseline data and outcomes for patients with urinary leakage were reported separately. No time limits were imposed regarding date of publication; however, outdated treatments were excluded. Eligible outcomes were episodes of incontinence/urinary leakage, quality of life and adverse events. We had no limit on the duration of treatment or follow-up time. Only studies written in English were included. In the present systematic review, older persons living in long-term care institutions were regarded as frail elderly. We did not find any studies on communitydwelling frail elderly. Inclusion criteria for the studies in the present systematic review: Patients • Patients aged 65 years or older with urinary incontinence (elderly) • Patients living in nursing homes (frail elderly) • At least 20 patients in the intervention group and 20 in the control group. Intervention • Treatment with one or more drugs for urinary incontinence • The study design should be a randomized controlled study or observational cohort study. Control • Treatment with placebo or other specified treatment. Outcomes • Urinary leakage, quality of life or adverse events.
Results All studies that met the inclusion criteria for the present review were randomized, placebo-controlled studies. A total of 13 studies of moderate or high quality were included, just three of which had a population of frail elderly. The characteristics and outcomes of the included studies are presented in Table 1. For UUI, we included studies for oxybutynin,23,27–29 tolterodine,30 fesoterodine,21 solifenacin,31,32 darifenacin22,24 and trospium.33 Two studies on duloxetine for SUI were also included.19,20 524 |
There were no publications on estrogen or mirabegron that fulfilled the inclusion criteria. The flow chart for inclusion of studies is presented in Figure 2.
Urgency urinary incontinence Frail elderly Three of the included publications described the effect of oxybutynin in frail elderly patients with urinary incontinence.27–29 Two of these publications were from the same study.28,29 In these two studies, the effect of oxybutynin versus placebo was evaluated in nursing home residents in the USA and included 200 participants. The results of these studies showed no effect of oxybutynin on urinary leakage in frail elderly patients, and they did not find any differences in adverse effects between the oxybutynin and placebo groups.
Elderly Eight studies evaluated the effect of anticholinergic drugs on urinary incontinence in elderly patients (not frail). The studies included 3253 patients from Asia, Australia, Europe, North and South America, and South Africa. The effects of the different drugs on urinary leakage and quality of life are presented in Table 2. The number of urinary leakages decreased for all drugs, except for oxybutynin. The absolute decrease corresponded to approximately half a leakage per 24 h, from a baseline frequency of approximately three leakages per 24 h. Three of the studies included validated assessments of health-specific quality of life; two of them used the OAB questionnaire,21,24 and one used the Kings Health Questionnaire.33 In the studies in which fesoterodine21 and darifenacin24 were evaluated, the OAB questionnaire improved significantly, but no significant improvement in Kings Health Questionnaire was shown when trospium was studied.33 The metaanalysis of the effect of anticholinergic drugs versus placebo is shown in Figure 3. Overall, a significant effect on the frequency of urinary leakage was found. Adverse effects were more frequent in the treatment groups. There was a similar pattern of adverse effects in studies of anticholinergics, except for oxybutynin. Dry mouth affected 11–32% of patients taking anticholinergics, compared with 0–8% in the placebo group. Corresponding percentages for constipation were 6–24% in the group taking the active drug and 0–8% in the placebo group. None of the studies included any specific assessments of cognition (Table 3). The overall assessment of the effects of treatment and the quality of evidence are presented in Table 4.
SUI Two studies evaluating the effect of duloxetine on SUI were included; there were a total of 500 participants © 2015 Japan Geriatrics Society
1.9 UUIE/24 h
No. IE/week: 18.3–21
>65 years with ≥1 UUI episode per 24 h 65–74 years, mean age 69.2 years ≥75 years, mean age 78.6 78% women
>65 years with OAB, at least 1 UUIE/24 h, capable of visiting a toilet unaided. Mean age: 71.6 years (range 65–88) 77.6% women
DuBeau et al. 201221 USA, Central and South America, Europe, Asia, South Africa.
Foote et al. 200522 Multicenter study >4 different countries
Severity of UI at baseline
Approximately 20 UUIE/week
Population Mean age Criteria for UI
Age ≥65 years, >1 UUIE/day Independent toileting. 77.4% women Mean age: 72 ± 5 years
Anticholinergic Chapple et al. 200724 USA, Poland, South Africa, Hungary, Sweden, UK, Germany
Study and country
© 2015 Japan Geriatrics Society Darifenacin 7.5 or 15 mg once daily 12 weeks I = 207 (no data) C = 110 (2)
Fesoterodine 4 mg daily 1 week, 8 mg daily 11 weeks 12 weeks I (65–74 years) = 379 (27) I (> 75 year) = 167 (11) C (65–74 years) = 199 (7) C (> 75 years = 107 (11)
Darifenacin 7.5 mg daily, voluntary up-titration to 15 mg after 2 weeks 12 weeks I = 266 (22) C = 133 (16)
Intervention and control n (dropouts)
Urinary leakage (12 weeks) UUIE/week: I, 19.8–14.0; C, 21.0–13.0; NS diff HLD = −1 (−2.83, 1) Responder rates ≥50% reduction from baseline in UUIE: I, 186 (70%); C, 77 (58%); RD = 0.12 (0.02, 0.22)* Quality of life (OABq) Week 6, mean change: I, 20.9; C, 15.3; P < 0.001; MD = 5.60 (2.27, 8.93)* Week 12, mean change: I, 22.9; C, 16.8; P < 0.001; MD = 6.10 (2.47, 9.73) Adverse effects (12 weeks) AAE: I, 149 (56.0%); C, 60 (45.1%); RD = 0.11 (0.01, 0.21)* Dry mouth: I, 59 (22.2%); C, 5 (3.8%); RD = 0.18 (0.12, 0.24)* Constipation: I, 41 (15.4%); C, 11 (8.3%); RD = 0.07 (0.01, 0.14)* Urinary leakage Difference vs placebo after 12 weeks 65–74 years, approx 1.9–1.6 UUIE/24 h, P = 0.0307 >75 years, approx 1.8–1.25 UUIE/24 h, P = 0.0594 Quality of life (OABq) HRQL (OABq) significant effect in both age groups (P = 0.0028 65–74 years, P = 0.0033 > 75 years) Adverse effects (12 weeks) Dry mouth: 65 − 74 years, 31.9% vs 6.0%; >75 years, 29.9% vs 5.6% Constipation: 65–74 years, 5.8% vs 2.5%; >75 years, 9.6% vs 1.9% Cognition: No cognitive adverse events >1% were reported in any group, no specific assessment of cognition Urinary leakage IE/week, (median reduction, 12 weeks) BL: 7.5 mg, 21.0; 15 mg, 17.2; C, 18.3 12 weeks: 7.5 mg, −11.2; C, 4.8; 15 mg, −10.8; C, −6.8 7.5 mg WMD = −5.9 (−9.1, −2.2)*** 15 mg WMD = −4.1 (−6.4, −1.6*** Quality of life No information Adverse effects AAE: C, 56 (50.9%); 7.5 mg, n = 52 (53.6%); 15 mg, n = 76 (69.1%); 7.5 mg RD = 0.03 (−0.11, 0.16); 15 mg RD = 0.18 (0.05, 0.31)* Dry mouth: C, 5 (5%); 7.5 mg, 20 (21%); 15 mg, 23 (31%); 7.5 mg RD = 0.16 (0.07, 0.25)*; 15 mg RD = 0.26 (0.17, 0.36)* Constipation: C, 7 (6); 7.5 mg, 18(19%); 15 mg, 26 (24%); 7.5 mg RD = 0.12 (0.03, 0.21)*; 15 mg RD = 0.17 (0.08, 0.26)*
Outcomes (95% CI)
Table 1 Drugs for urinary incontinence in the elderly: summary of included studies (n = 13)
Moderate RCT Sub group analysis Sponsored by Pfizer, Novartis Pharma, Thomson Acumed.
Moderate Post-hoc analysis of subjects aged ≥65 years; pooled data from two RCT Sponsored by Pfizer
High RCT Masked random allocation, large number of patients, well described RCT, appropriate outcomes Sponsored by Novartis Pharmaceuticals
Quality of study Comments
Pharmacotherapy of geriatric incontinence
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526 | Trosphium chloride 60 mg ER once daily 12 weeks I = 85 (11) C = 58 (8)
Median UUIE/week: I: 22.17, C: 16.33
OAB > 6 months ≥3 episodes of UUI/3 days Age >75 years, Mean age: 79 years 73% women
Sand et al. 201133 USA
Oxybutynin 2.5–5 mg × 3 + prompted voiding 20 days Cross-over to placebo + prompted voiding I = 75 (12) C = 75 (12)
8.6 ± 3.4 IE/3 days
Nursing home residents with UUI, at least one “wet check” per day. Mean age: 85.6 ± 8.6 years Ability to say his/her name or reliably point one of two objects.
Ouslander et al. 199527 USA
Intervention and control n (dropouts) Oxybutynine 5 mg extended-release once daily during four weeks, placebo controlled I = 26 (1) C = 24 (2)
Female nursing home residents ≥65 years with UUI MMSE 5–23 Mean age: 88.6 ± 6.2 years
Lackner et al. 200828 Lackner et al. 201129 USA
Severity of UI at baseline 6.8–9 UIE/day
Population Mean age Criteria for UI
Study and country
Table 1 Continued
Urinary leakage UIE: No. wet hourly pad checks, 8 am to 4 pm two consecutive days, median (% change) BL: I, 6; C, 4.5 4 weeks: I, 2 (−38%); C, 2.5 (−53%), P = 0.97, MD = −8.07 (−37.84, 21.71) Quality of life No information Adverse effects CAM score change from baseline BL: I, 2.0; C, 1.8 Day 28: I, −0.6; C, −0.5 Treatment difference = 0.167 (−0.7, 1) Median change MMSE score: day 28, P = 0.98 Median change SIB score: day 28, P = 0.62 Agitation BARS score: No group differences in the mean BARS score change at any time-point (P = 0.50–0.94) Adverse events (4 weeks) AAE: I, 8(31%); C, 9 (38%); RD = −0.07 (−0.33, 0.20) Constipation: I, 2 (8%); C, 0; RD = 0.08 (−0.05, 0.20) Dry mouth: I, 1 (4%); C, 1 (4%); RD = −0.00 [−0.11, 0.11] Confusion: I, 0; C, 1 (4%); RD = −0.04 (−0.15, 0.06) Urinary leakage (day 20) No. IE/3 days BL: 8.6 Day 20: I, 6.8; C, 7.7; MD = −1.10 (−2.39, 0.19) Quality of life No information Adverse effects AAE: RD = 0.02 [−0.01, 0.05] Constipation: I, 16 (30%); C, 13 (25%); RD = 0.06 (−0.11, 0.23) Dry mouth: I, 22(42%); C, 19 (35%); RD = 0.07 (−0.11, 0.26) Urinary leakage (12 wk) Change in mean number of UUIE/wk: I, 22.17 (69.9% reduction); C, 16.33 (25% reduction); P = 0.04 Quality of life Only significant difference was in severity measures domain: I, −8.08 (SE 1.02); C, −5.63 (1.31); P = 0.03; OABq MD = −2.45 (−5.70, 0.80) Greater numerical increase in I vs C, P = 0.02 Adverse effects (12 weeks) Constipation: I, 9(10.6%); C, 0; RD = 0.11 (0.04, 0.18)* Dry mouth: I, 9 (10.6%); C, 2 (3.4%); RD = 0.07 (−0.01, 0.15)
Outcomes (95% CI)
Moderate RCT Subgroup analysis with pooled data from two studies. Results from the placebo-controlled part of the study are reported in this table. Study sponsored by Allergan, Inc and Endo Pharmaceuticals Inc.
Moderate RCT Very frail elderly Difficult to reliable ascertain side effects because of severe cognitive impairment.
Moderate RCT Few patients available for assessment of adverse effect on cognition Sponsored by research grant from Ortho-McNeil Pharmaceutical
Quality of study Comments
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© 2015 Japan Geriatrics Society
I: 10 UIE daytime/week C: 7 UIE daytime/week
2.9 ± 0.2 UIE/24 h
23 UIE/week
Outpatients ≥70 years, symptoms of urinary frequency, urgency and urge incontinence. Mean age: 82 ± 6 years 95% women MMSE score: 28 ± 7.6
≥8 micturition/day and mean of ≥1 UI/day or mean of ≥1 UUIE/day Mean age: 71.9 years 74.5% women
>5UUIE/week, >8 micturitions/24 h Mean age: 74 ± 6 years 74.4% women
Szonyi et al. 199523 UK
Wagg et al. 200632 Cardozo et al. 200631 UK, USA, France
© 2015 Japan Geriatrics Society
Zinner et al. 200230 Europe, USA, Canada, Australia, and New Zealand Tolterodine ER capsules 4 mg once daily 12 weeks I = 214 (21) C = 223 (29)
Solifenacin 5 mg or 10 mg 12 weeks I (5 mg) = 192 (9) I (10 mg) = 431 (40) C = 422 (23)
Oxybutynin 2.5 mg twice daily and bladder training, placebo controlled 6 weeks I = 30 (8) C = 30 (5) Urinary leakage Micturition chart: C, 28; I, 24 Change in IE/day during first 14 days vs last 14 days Median change: −9.5 (−11, 3) I, 10–8 (difference 8); C, 7–7 (difference 7) Quality of life No information Complications/adverse effects (insufficient data, no. patients not given) Dry mouth: I, 93%; C, 86%; RD = 0.07 (−0.08, 0.22) Constipation: I, 50%; C, 45%; RD = 0.03 (−0.22, 0.29) Urinary leakage IE/day (mean change from baseline) Baseline; change after 12 weeks 5 mg: 2.5;-1.5 10 mg: 3.0;-1.9 C: 3.0;-1.0 5 mg MD = −0.63 (−1.12, −0.13)*; 10 mg MD = −0.86 (−1.19, −0.54)* Quality of life No information Adverse events (12 weeks) Dry mouth: 5 mg, 26 (13.5%); 10 mg, 136 (31.6%); C, 20 (4.7%); 5 mg RD = 0.09 (0.04, 0.14)*; 10 mg RD = 0.27 (0.22, 0.32)* Constipation): 5 mg, 18 (9.4%); 10 mg, 78 (18.1%); C, 18 (4.3%); 5 mg RD = 0.05 (0.01, 0.10)*; 10 mg RD = 0.14 (0.10, 0.18)* Urinary leakage (12 weeks) IE/week (mean reduction): I, 23.2–11.5; C, 23.4–6.3; MD = −5.20 (−8.33, −2.07)* Quality of life No information Complication/adverse effects (12 weeks) AAE: I, 116 (54.2%); C, 102 (46.0%), RD = 0.08 (−0.01, 0.18) Dry mouth: I, 52 (24.3%); C, 16 (7.2%); RD = 0.17 (0.10, 0.24)* Constipation: I, 13 (6.1%); C, 10 (4.5%); RD = 0.02 (−0.03, 0.06)
High RCT Sponsored by Pharmacia
Moderate Retrospective analysis of pooled data from four studies Sponsored by Yamanouchi Pharmaceuticals
Moderate RCT Sponsored by Smith&Nephew Pharmaceuticals Ltd
Pharmacotherapy of geriatric incontinence
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528 | 24 UUIE/week
Mean UIE/week at baseline I: 20.5, C: 21.6
Women ≥65 years with SUI ≥7 UIE/week Mean age not known
Severity of UI at baseline
Community-dwelling women, aged ≥65 years SUI or stress-dominant MUI. ≥7 UIE/week. MMSE > 80) Mean age: 71 years No cognitive impairment: 79.25%
Population Mean age Criteria for UI
Duloxetin 40 mg twice daily 12 weeks I = 111 (no information of drop-outs for age group >65 years, 28% dropout for the whole group). C = 124 (no information)
Duloxetine 20 mg twice daily 40 mg twice daily De-escalation/discontinuation phase. 2 + 10 + 4 weeks. I = 134 (22) C = 131 (17)
Intervention and control n (dropouts)
Urinary leakage Change in mean IEF/week (24-h diaries) 6 weeks: I, −11.7; C, −6.9 Absolute change: MD = −4.80 (−7.66, −1.94)* IEF responder rate (reduction ≥50%): I, 72(57%); C, 43 (35%); P < 0.001 CS; RD = 0.22 (0.10, 0.34)* Quality of life (16 weeks) I-QOL, mean change, total score: I, 12.81; C, 6.84; MD = 5.97 (2.41, 9.53)*; P < 0.001 Responder rate I-QOL, percentage of patients with increase in I-QOL total score of ≥6.3: I, 69 (55%); C, 59 (48%); RD = 0.06 (−0.06, 0.19) Adverse effects (16 weeks) Dry mouth: I, 26 (19.4%), C, 2 (1.5%); RD = 0.18 (0.11, 0.25)* Constipation: I, 14 (10.4%), C, 1 (0.8%); RD = 0.10 (0.04, 0.15)* Urinary leakage IEF/week Median change (%): I, −43.75; C, −22.95; P = 0.052 Quality of life I-QOL, mean change (12 weeks): I, 61.4 + 9.4; C, 59.6 + 5.8; P = 0.043; MD = 3.54 (−0.34, 7.42) Adverse effects Adverse effects were not significantly different in women of different ages, but there was no specific information on adverse events for the age group >65 years
Outcomes (95% CI)
Moderate RCT Small absolute effects, clinical relevance. Post-hoc analysis of subgroup ≥65 years from four controlled trials. Higher dropout rate for the intervention vs control group for all ages. Both authors are fully employed by Eli Lilly and Company and hold stock and stock options in the company
High RCT, masked random allocation, blinded, adequate outcome variables described with absolute and relative data Sponsored by Eli-Lilly and Boehringer Ingelheim
Quality of study Comments
*P < 0.05, ***P < 0.001. AAE, any adverse effects; AD, ANCOVA difference; AE, adverse effects; AMD, adjusted mean difference; BARS, Brief Agitation Rating Scale; BL, baseline; BT, bladder training; C, control; CAM, confusion assessment method; CS, clinical sign; F/M, female/male; GDS, Global Deterioration Scale; HLD, Hodges–Lehmann difference; HRQL, health related quality of life; I, intervention; IE, incontinence episodes; IEF, incontinence episode frequency; I-QOL, Incontinence quality of life; MD, mean difference; MMSE, mini-mental state examination; MMSS, mini-mental state score; MUI, mixed urinary incontinence; NH, nursing home; NS, non-significant; OAB, over active bladder; OABq, overactive bladder questionnaire; PFMT, pelvic floor muscle training; PV, prompted voiding; PVR, post-void residual urinary volume; PVR, post-void residual volume; QOL, quality of life; RCT, randomized controlled trial; RD, risk difference; SE, Standard error; SIB, Severe Impairment Battery; SUI, stress urinary incontinence; UF, urinary frequency; UI, urinary incontinence; UIE, urinary incontinence episodes; UTI, urinary tract infection; UUI, urgency urinary incontinence; UUIE, urgency urinary incontinence episodes; WMD, Wilcoxon rank-sum test median difference.
Viktrup and Yalcin 200720 Africa, Australia, Europe, North America and South America
Duloxetine Schagen van Leeuwen et al. 200819 Germany, France, Netherlands, Spain, Sweden, Switzerland, South Africa
Study and country
Table 1 Continued
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Pharmacotherapy of geriatric incontinence
Figure 2 studies.
Flowchart of included
from Australia, Africa, Europe, and North and South America.19,20 Schagen van Leeuwen et al. studied patients with UI, but just 40% of the included women had SUI, 7% UUI and the rest had MUI.19 There was a significant decrease in the number of urinary leakages in the treatment group compared with placebo (duloxetine: −11.7 urinary leakage episodes per week compared with placebo: −6.9, P = 0.0010). However, when only patients with SUI were analyzed, no effect on urinary leakage was found. Viktrup et al. showed no effects on the number of urinary leakages (duloxetine: −6.6 urinary leakage episodes per week compared with placebo: −3.6, P = 0.052). In the study by Schagen van Leeuwen et al., adverse effects (i.e. dry mouth, fatigue, constipation and hyperhidrosis) were more frequent in the treatment group. There were no data on adverse effects reported separately for the elderly in the study by Viktrup et al. In both studies, however, there was an improvement in quality of life (measured by I-QOL-score) in the treatment group, but the clinical significance of this small difference is unclear (Table 1).
Risk of bias in the included studies All 13 studies were placebo-controlled, and randomization was carried out on an individual basis. Although they all stipulated that the allocation procedure was © 2015 Japan Geriatrics Society
correct, it was not described in detail in all studies. Five studies did not report whether assessors were blinded to the treatment status of the participants and one of them contained no information of blinding at all. 20,21,31–33 The number of dropouts was generally small or moderate without any important difference between groups. However, of the six studies based on post-hoc data from the elderly, just two had complete information on dropouts and withdrawals.20–22,31–33 The compliance to treatment was acceptable where it was reported.22–24,28–30 Compliance varied between 80–100% of participants taking more than 75% of prescribed doses. Pharmaceutical companies sponsored all of the studies but one.27
Discussion In the present systematic review, we found that treatment with anticholinergic drugs decreased the number of urinary leakages in elderly patients with UI. The effect in absolute numbers of urinary leakages is small – corresponding to half a leakage per 24 h. For anticholinergic drugs, adverse events such as dry mouth and constipation were more frequent compared with placebo. The effect of treatment with anticholinergics on quality of life remains unclear in elderly patients. Furthermore, there were no positive effects of | 529
530 | 887 (2 RCT)
852 65–74 years: 578 > = 75 years: 274 (1 RCT) 57 (1 RCT) 689 (1 RCT, 2 publications)
437 (1 RCT) 139 (1 RCT)
Darifenacin (Foote et al. 200522; Chapple et al. 200724)
Fesoterodine† (DuBeau et al. 201221)
Tolterodine (Zinner et al. 200230) Trospium (Sand et al. 201133)
23 per week 16.3–22.1 UIE/week
8 UI daytime/week 2.9 ± 0.2 UIE/24 h
17.2–21 UIE/week Not presented in Chapple 17 UI/week
Incontinence episode frequency at baseline
NS 5 mg solifenacin: 0.5 UI/24 h* 10 mg solifenacin: 0.9 UI/24 h* 0.7/24 h* 1.2/24 h*
Foote: 0.7/24 h* Not presented in Chapple 65–74 years: 0.3/24 h* ≥75 years: NS
Absolute decrease in number of incontinence episodes (treatment – placebo)
No data No significant improvement KHQ
No data No data
OABq significant improvement in 65–74 years, as well as ≥75 years
OABq significant improvement
Quality of life
*P < 0.05. †In this study, fesoterodine is compared with placebo and with tolterodine. As tolterodine is not compared with placebo, only participants on fesoterodine or placebo are included here. KHQ, Kings Health Questionnaire; OABq, overactive bladder questionnaire; RCT, randomized controlled trial; UIE, urinary incontinence episodes.
Oxybutynine (Szonyi et al. 199523) Solifenacin (Cardozo et al. 200631; Wagg et al. 200632)
No. patients (no. studies and study design)
Drug
Table 2 Effects of anticholinergic drugs in elderly (not frail elderly) with urgency urinary incontinence; urinary leakage and quality of life
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Pharmacotherapy of geriatric incontinence
Figure 3
Improvement in number of urinary leakages in the elderly; anticholinergic drugs versus placebo.
anticholinergics on UI in frail elderly in the two studies that were included. The evidence is insufficient to evaluate the effects of duloxetine on SUI in the elderly. Just two studies on SUI fulfilled our inclusion criteria, and neither of them showed that duloxetine had an effect on the number of urinary leakages in patients with SUI. There were no studies that compared a standard-of-care group (i.e. pelvic floor muscle training). Different kinds of measurements for quality of life, adverse effects and symptoms of UI make it difficult to compare the results of different studies. Furthermore, results regarding adverse effects might not be applicable for the general population of the elderly. Not all studies reported whether the participants had been treated with anticholinergic treatment for UUI before entering the study or not; if the participants had previous treatment, it could indicate a selection of participants that already tolerate the drugs. In the present systematic review, studies on adverse effects were not included unless results were reported separately for OAB patients with incontinence. However, there might be other studies on adverse effects of anticholinergics in OAB patients. Limitations of our review include the low number of studies on frail elderly individuals that we included and © 2015 Japan Geriatrics Society
the pragmatic definition of frailty (i.e. “nursing home residents”) that we used. There are two common definitions of physical frailty. According to Fried et al., frailty includes three or more of five symptoms: unintentional weight loss, exhaustion, weakness, slow walking speed and low physical activity.34 The other definition is based on the Frailty Index, where the number of impairments and conditions of the individual are added to create an index.35 Frailty is a state with increased vulnerability to stressors, and it is associated with increased mortality, especially in women.36,37 Frail individuals are therefore seldom included in drug trials. None of the studies we found on elderly individuals living in their own homes included an assessment of frailty. The present review on pharmacotherapy for urinary incontinence in frail elderly individuals was therefore limited to the few studies in which nursing home residents were assessed. In the elderly, and especially the frail elderly, the effect of medications on cognition is of great importance. It is well settled that anticholinergic drugs can have adverse effects on cognition in the elderly, but it has not yet been convincingly shown that discontinuation is associated with an increase in cognitive performance.38,39 There was a lack of adequate assessment of cognition in | 531
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Table 3 Adverse effects in elderly with urgency urinary incontinence treated with anticholinergics Drug
No. patients Dry mouth (no. studies and study design)
Darifenacin (Foote et al. 200522; Chapple et al. 200724) Fesoterodine† (DuBeau et al. 201221)
887 (2 RCT)
31% vs 5%* 24% vs 6%* 22.2 vs 3.8%* 15.4% vs 8.3%* RD = 0.20 (0.14, 0.25)* RD = 0.11 (0.06, 0.17)
852 (1 RCT)
65–74 years: 31.9% vs 6.0% ≥75 years: 29.9% vs 5.6%
Oxybutynine (Szonyi et al. 199523)
57 (1 RCT)
Solifenacin (Cardozo et al. 200631; Wagg et al. 200632) Tolterodine (Zinner et al. 200230)
689 (1 RCT, 2 publications) 437 (1RCT)
Trospium (Sand et al. 139 (1 RCT) 201133)
Constipation
Cognition
No data
65–74 years: 5.8% vs No cognitive adverse 2.5% events reported in any group, but no ≥75 years: 9.6% vs 1.9% specific assessment of cognition 93% vs 86% 50% vs 45% No data RD = 0.07 (−0.08, 0.22) RD = 0.03 (−0.22, 0.29) NS NS 31.6% vs 4.7%* 18.1% vs 4.3%* No data RD = 0.27 (0.22, 0.32) RD = 0.14 (0.10, 0.18) 24.3% vs 7.2%* RD = 0.17 (0.10, 0.24)
6.1% vs 4.5% RD = 0.02 (−0.03, 0.06) NS 10.6% vs 3.4% 10.6% vs 0%* RD = 0.07 (−0.01, 0.15) RD = 0.11 (0.04, 0.18) NS
No data
No data
*P < 0.05. †No P-value presented. RCT, randomized controlled trial.
Table 4 Overall assessment of the effects of treatment with anticholinergics drugs in the elderly with urgency urinary incontinence Effects
No. patients, studies and design
Overall assessment
Quality of evidence
Urinary leakage
2894 (7 RCT)
⊕⊕⊕
Quality of life
1375 (3 RCT)
Dry mouth Constipation Cognition
2960 (7 RCT) 2960 (7 RCT) No studies with assessment of cognition
No. UIE decrease with approximately half a leakage per 24 h Conflicting results; three studies with data on QOL, improvement in two of them 11–32% compared with 3–7% in placebo group 6–24% compared with 0–8% in placebo group Not possible to assess. Lack of studies.
⊕ ⊕⊕⊕ ⊕⊕⊕ ⊕
QOL, quality of life.
the included studies. One reason might be that there is no consensus of how to assess cognitive impairment.40 The follow-up period in the included studies was usually 12 weeks. Thus, the long-term effects of these anticholinergic drugs on UI have not been evaluated at all. An increase in mortality has previously been shown for long-term exposure of anticholinergic drugs.41 For mirabegron and estrogen, there were no studies that fulfilled our inclusion criteria. Estrogen is often 532 |
used in older women with UI, but the evidence supporting this use is scarce. Mirabegron is a relatively new drug, and there are no studies in the elderly, yet. Future studies are warranted to evaluate the effects and adverse effects of drugs on UI in the elderly, and especially in the frail elderly. Standardization of measurements for quality of life, adverse events and symptoms of UI would also greatly benefit this field of research. There is also a need for long-term studies, as © 2015 Japan Geriatrics Society
Pharmacotherapy of geriatric incontinence
well as studies that compare the effects of pharmacological treatment with the effects of nonpharmacological treatment.
Conclusion Anticholinergic drugs have a small, but significant, effect on urinary leakage in the elderly with urgency urinary incontinence. Adverse effects, such as dry mouth and constipation, were common, but none of the studies included a thorough assessment of cognition. Treatment with anticholinergics for UUI in the frail elderly is not evidence based. Further studies are required to evaluate the effects of duloxetine, mirabegron and estrogen in the elderly population.
Acknowledgments This study was financially supported by the Swedish Council on Technology Assessment in Health Care. We are grateful to Elisabeth Gustafsson for help with administration of the project.
Disclosure statements No potential conflicts of interest were disclosed.
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Supporting information Appendix S1 Search strategies. Appendix S2 List of excluded articles.
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