Drug treatment for lower urinary tract symptoms in women with voiding dysfunction

  • Protocol
  • Intervention

Authors

  • Zhan-Miao Yi,

    1. Peking University Third Hospital, Department of Pharmacy, Beijing, China
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  • Rong-Sheng Zhao,

    1. Peking University Third Hospital, Department of Pharmacy, Beijing, China
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  • Suo-Di Zhai,

    Corresponding author
    1. Peking University Third Hospital, Department of Pharmacy, Therapeutic Drug Monitoring and Clinical Toxicology Center of Peking University, Beijing, China
    • Suo-Di Zhai, Department of Pharmacy, Therapeutic Drug Monitoring and Clinical Toxicology Center of Peking University, Peking University Third Hospital, 49 North Garden Rd, Haidian District, Beijing, 100191, China. zhaisuodi@163.com.

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  • Guo-Liang Wang

    1. Peking University Third Hospital, Department of Urinary Surgery, Beijing, China
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Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To determine the effectiveness and safety of drugs to treat LUTS in women with voiding dysfunction.

Background

Description of the condition

As the world's population ages, more and more people will develop lower urinary tract symptoms (LUTS), which will diminish their quality of life. LUTS can be classified into three types: storage, voiding, and post-micturition symptoms (Abrams 2003). According to the International Urogynecological Association and the International Continence Society, voiding dysfunction is defined as abnormally slow and/or incomplete micturition based on symptoms and/or urodynamic investigations (Haylen 2010).

The prevalence of female voiding dysfunction is various, from 2.7 to 23 % (Choi 2013). A large survey in Canada, Germany, Italy, Sweden and the United Kingdom showed that men (25.7%) reported voiding symptoms more than women (19.5%) (Irwin 2006). Pelvic floor disorders, urogenital prolapse > stage II, symptoms of voiding difficulty, age > 55 years, prior incontinence surgery, a history of multiple sclerosis and the absence of stress urinary incontinence are risk factors for voiding dysfunction (Robinson 2012).

Patients with voiding dysfunction comprise a significant proportion of people with complicated urinary tract infections (Neal 2008). An increase in postvoid residual urinary volume (for example, > 50 mL) is an independent risk factor for recurrent urinary tract infections in postmenopausal women (Kodner 2010). Furthermore, insufficient bladder voiding can lead to renal damage, for example in caudal regression syndrome patients (Torre 2011).

Voiding dysfunction can manifest as a broad spectrum of symptoms including urinary hesitancy, slow stream, intermittency, straining to void, spraying, incomplete bladder emptying, need to immediately re-void, post-micturition leakage, position-dependent micturition and dysuria (Robinson 2012). Voiding dysfunction can be caused by either detrusor underactivity and/or bladder outlet obstruction (Raheem 2013).

The common causes of female detrusor underactivity include the following:

  • neurogenic (cerebral, spinal sacral and subsacral lesions);

  • myogenic (aging and acute prolonged bladder overdistension); and

  • mixed other risk factors (e.g. diabetic cystopathy).

The pathogenesis of female bladder outlet obstruction can be anatomical (for example, pelvic organ prolapse) or functional (for example, dysfunctional voiding) (Raheem 2013).

Description of the intervention

For therapy, it might not be possible to achieve a complete cure for patients with voiding dysfunction. Therefore, the goal of symptom relief may be acceptable.

Women with an acontractile bladder detrusor muscle (detrusor underactivity) can be offered the below treatment options:

  • behavioural therapy;

  • pharmacotherapy;

  • intravesical electrical stimulation;

  • clean intermittent self-catheterisation;

  • sacral neuromodulation;

  • surgical treatment.

For women with mechanical bladder outlet obstruction, clean intermittent catheterisation or a suprapubic catheter can be offered if it is not possible to correct the cause of the obstruction, for example with surgery for pelvic organ prolapse (Raheem 2013).

The availability of effective pharmacological treatment, direct-to-consumer outreach by pharmaceutical industries, the relative frequency of side effects with surgery, and an increasing focus on quality of life have all led to a steady decrease in the number of surgical procedures performed and an increase in the use of drugs (pharmacological treatment) for voiding dysfunction in the US, Europe, and other parts of the world (Chapple 2012).

Drug treatment for female voiding dysfunction

The pharmacological treatment of female voiding dysfunction varies depending on the underlying pathophysiology. Pharmacological intervention for women with detrusor underactivity focus on increasing bladder contractility by increasing detrusor strength, decreasing outflow resistance, or both.

How the intervention might work

Voiding dysfunction may be treated by drugs that either increase the detrusor contractile force and/or decrease outflow resistance, thereby restoring an appropriate balance between detrusor strength and urethral resistance.

Increasing detrusor strength

Muscarinic receptor agonists and choline esterase inhibitors have been found to enhance detrusor strength (Raheem 2013). Muscarinic receptor agonists (for example, bethanechol and carbachol) may stimulate the detrusor cells causing an increase in bladder contractility. Moreover, choline esterase inhibitors (for example, distigmine, pyridostigmine and neostigmineacetyl) can activate the endogenous agonist acetylcholinesterase to provide additional stimulation of muscarinic receptors on the detrusor cells (Barendrecht 2007).

Decreasing outflow resistance

Female bladder outlet obstruction is relatively uncommon, but the condition may coexist with detrusor underactivity. Drugs that decrease outflow resistance (for example, alpha-1-adrenoreceptor antagonists) may restore the balance between detrusor strength and urethral resistance (Koeveringe 2011). Alpha-1-adrenoreceptor antagonists can increase smooth muscle relaxation and improve urinary flow by blocking noradrenaline from binding to and stimulating alpha1-adrenoreceptors in the bladder neck (as well as the prostate and prostatic urethra) so as to relieve bladder outlet obstruction (Meyer 2012). Thus, while alpha-1-adrenoreceptor antagonists might be efficacious for primary bladder outlet obstruction, they may also increase the risk of stress urinary incontinence by reducing urethral resistance (Raheem 2013).

Why it is important to do this review

The above interventions are currently used for the treatment of voiding dysfunction, but few studies on their effectiveness and safety have been conducted, resulting in a lack of evidence and hence uncertain recommendations for clinicians and patients.

A search of The Cochrane Library revealed no published systematic reviews of drug treatment for LUTS in women with voiding dysfunction. If there is evidence that pharmacological treatment is effective, this could add an important treatment modality to the overall management of voiding dysfunction. Furthermore, the best available evidence on the cost-effectiveness of alternative treatment strategies will be summarised and the findings will help decision makers to consider the maximisation of health benefit within the confines of scarce healthcare budgets.

We are aware of a Cochrane protocol covering non-drug treatment for lower urinary tract symptoms in women with voiding dysfunction, which is currently being developed (Hajebrahimi ongoing). Other related reviews that may be of interest to the reader include:

  • surgical and conservative management of pelvic organ prolapse (Hagen 2011; Maher 2013);

  • urinary diversion for intractable incontinence or after cystectomy (Cody 2012);

  • surgery and self dilatation for urethral strictures in men (Jackson 2012; Wong 2012); and

  • surgical management of bladder outlet obstruction in neurogenic bladder dysfunction (Utomo 2011).

Objectives

To determine the effectiveness and safety of drugs to treat LUTS in women with voiding dysfunction.

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials (RCTs) or quasi-RCTs of drugs for LUTS in women with voiding dysfunction.

Types of participants

We will include studies which include participants with a definite diagnosis of voiding dysfunction according to the International Urogynecological Association or the International Continence Society terminology report (Haylen 2010), or reasonable clinical criteria for the diagnosis of voiding dysfunction. We will include all RCTs of female voiding dysfunction regardless of the particular aetiologies (e.g. inclusive of women with voiding dysfunction related to MS, spinal cord injury or prolapse).

We will consider only female participants. RCTs that included both men and women, but presented separate results for women, will be included. There will not be any other inclusion restrictions on the basis of participant and study characteristics, such as duration of the trials or age.

Types of interventions

Any pharmacological treatment versus placebo, versus no intervention or versus another treatment (for example another kind of pharmacological treatment or a mechanical intervention).

We will consider the following comparisons:

  1. drugs versus placebo or no treatment;

  2. one class of drug (e.g. muscarinic agonists, adrenergic antagonists) versus another class of drug;

  3. one dose of a drug versus another;

  4. one frequency of administration of a drug versus another;

  5. one route of administration of a drug versus another;

  6. drugs versus conservative physical treatments (e.g. bladder reflex triggering);

  7. drugs versus catheters (indwelling, intermittent);

  8. drugs versus electrical stimulation (non-invasive, implanted).

Types of outcome measures

Primary outcomes
  • Number of women with voiding dysfunction

  • Voiding dysfunction symptom scores

Secondary outcomes
  • Participant's observations

    • Number of women with voiding dysfunction not improved

    • Satisfaction with treatment

  • Quantification of symptoms

    • Flow rates

    • Post void residual volume

    • Incomplete bladder emptying

    • Retention

    • Voided volumes or changes in voided volumes (e.g. from urinary diaries)

  • Quality of life

    • General health status measures (e.g. Short-Form Health Survey 36 (SF-36) (Ware 1992))

    • Condition-specific health measures (specific instruments designed to assess impact of voiding dysfunction on quality of life)

  • Economic measures

    • Costs of interventions

    • Cost-effectiveness of interventions

    • Resource implications

  • Adverse effects

    • Number of women with urinary tract infections

    • Drug side effects (e.g. hypotension)

Search methods for identification of studies

We will not impose any language or other restrictions on any of the searches described below.

Electronic searches

This review will draw on the search strategy developed for the Cochrane Incontinence Group. We will identify relevant trials from the Cochrane Incontinence Group Specialised Register. For more details of the search methods used to build the Specialised Register please see the Cochrane Incontinence Group's module in The Cochrane Library (http://onlinelibrary.wiley.com/o/cochrane/clabout/articles/INCONT/frame.html). The Cochrane Incontinence Group Specialised Register contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 1999 onwards), MEDLINE (1966 to present), MEDLINE in process (2001 onwards) and handsearching of journals and conference proceedings. The terms to be used to search the Cochrane Incontinence Group Specialised Register are given in Appendix 1.

We will perform other specific searches of CENTRAL, MEDLINE, and EMBASE using search terms covering the concepts of: female, women, woman, voiding dysfunction, drug treatment, medication, pharmacotherapy, pharmacological, medicine.

We will identify unpublished trial data and ongoing trials from ClinicalTrials.gov (http://clinicaltrials.gov/) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) Search Portal (http://apps.who.int/trialsearch/).

Searching other resources

We will search other resources in an effort to identify published, unpublished and ongoing trials as follows:

  1. check reference lists of all relevant articles;

  2. contact the authors of trials, known experts in the field and pharmaceutical companies.

Data collection and analysis

Selection of studies

Two review authors (ZMY, RSZ) will independently check the titles and abstracts identified from the literature review. The review authors will obtain the full text of all potentially relevant studies for independent assessment. All review authors will resolve differences about inclusion of studies by discussion.

Data extraction and management

Two review authors (ZMY, RSZ) will extract data independently onto a specially designed form that will be piloted prior to use, and the other authors will check the data extraction. One review author will enter the data into the Cochrane Collaboration statistical software, Review Manager 2014, and one will check the data entered (RSZ). We will contact trial authors to obtain missing data whenever possible.

Assessment of risk of bias in included studies

Two authors (ZMY, RSZ) will independently assess all included studies for risk of bias according to the guidance in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will assess RCTs for:

  • random sequence generation,

  • allocation concealment,

  • blinding of participants or personnel,

  • blinding of outcome assessors,

  • incomplete outcome data,

  • selective outcome reporting and

  • other sources of bias.

Our judgements will be 'Low risk of bias', 'High risk of bias' or 'Unclear risk of bias'.

Measures of treatment effect

We will analyse all the primary and secondary outcomes under consideration. We will calculate weighted treatment effects across trials using Review Manager 2014. We will express results as risk ratios (RRs) with 95% confidence intervals (CIs) and risk differences (RDs) with 95% CIs for dichotomous outcomes, and mean differences (MDs) and 95% CIs for continuous outcomes.

Unit of analysis issues

For RCTs comparing more than two intervention groups, we will compare each intervention in a pair-wise manner with the others. We will include cross-over studies in which each participant acts as his or her own control and in which every participant receives every intervention. The effect estimate for the meta-analysis will be the mean and standard error (SE) of the differences between experimental and control groups. If appropriate, we will include the effect estimate in a meta-analysis using the generic inverse variance method in Review Manager 2014.

In cluster-randomised studies, groups of individuals are randomised to different interventions. We will use multi-level statistical models in the analysis of cluster-randomised trials. We will pool effect estimates and their SEs from correct analyses of cluster-randomised trials using the generic inverse variance method in Review Manager 2014.

Dealing with missing data

We will write to the authors of trial reports by email to try to obtain missing data. We will perform all analyses in accordance with the intention-to-treat method, which includes all randomised participants in the groups to which they were randomised, regardless of loss to follow-up or crossover to another treatment. Data will be used as reported by trialists unless there is evidence of differential drop-outs, in which case we will consider sensitivity analyses for different scenarios, such as all missing data are 'failed'. We will address potential implications of missing data (e.g. no outcome obtained, receiving the wrong treatment, lack of compliance, or ineligibility) in sensitivity analyses.

Assessment of heterogeneity

We will explore statistical heterogeneity among results of different studies using the Chi2 test with significance set at P value < 0.1. We will measure the percentage of variation between trial results that is due to heterogeneity rather than chance using the I2 statistic, with a value greater than 50% indicating substantial heterogeneity.

Assessment of reporting biases

We will draw a funnel plot to detect the possibility of publication bias in the meta-analysis if there are a reasonable number of studies (at least 10 are necessary for a clear pattern to emerge) (Higgins 2011). If meta-analysis of data is not possible, we will identify and report on any selective reporting in the included trials, although we are aware that this method is not a reliable indicator of publication bias and we will make any interpretations with great caution.

Data synthesis

We will not combine data from studies with different interventions, but we will consider group analyses of agents from the same class (e.g. pooling of data for the different alpha-1-adrenoreceptor antagonists). We plan to undertake a meta-analysis should sufficient studies be identified. If there is more than one trial with a specific treatment or class of treatments with similar actions and comparable outcome measures and no significant heterogeneity, we will use a fixed-effect model to combine trial results; otherwise, we will use a random-effects model.

Subgroup analysis and investigation of heterogeneity

If data are available, we will perform subgroup analyses to explore possible sources of clinical heterogeneity with regard to treatment. We will investigate relationships between intervention effect and dose, treatment intensity or treatment duration.

We will conduct subgroup analyses according to different causes (for example, neurogenic versus non-neurogenic), different treatments or comparisons, and according to the different underlying conditions (e.g. age of participants).

Sensitivity analysis

We will perform sensitivity analyses by repeating the meta-analyses after omitting trials in which a possible high risk of bias is identified in an important factor.

Acknowledgements

We are grateful to Dr. Muhammad Imran Omar and Professor Charis Glazener for patiently guiding us through the preparation of the protocol. We thank the Cochrane Incontinence Review Group for their ongoing support.

Appendices

Appendix 1. Search strategy - Cochrane Incontinence Group Specialised Register

The following search strategy will be used:

({TOPIC.URINE.BLADDER NECK DYSSYNERGIA.} OR {TOPIC.URINE.BladderOutletObstruction*} OR {TOPIC.URINE.DESD.} OR {TOPIC.URINE.RETENT.AcontractileBladder.} OR {TOPIC.URINE.RETENT.cath.} OR {TOPIC.URINE.RETENT.cath.infection.} OR {topic.urine.retent.chronic.} OR {TOPIC.URINE.RETENT.DetrusorUnderactive.} OR {TOPIC.URINE.RETENT.DysfunctionalVoiding.} OR {TOPIC.URINE.RETENT.HypocontractileBladder.} OR {TOPIC.URINE.RETENT.sphincterRelaxation.} OR {TOPIC.URINE.UnderactiveDetrusor.} OR {TOPIC.URINE.BLADDER CAPACITY.} OR {topic.urine.bladderDrainage.} OR {TOPIC.URINE.BladderNeckDysfunction.} OR {TOPIC.URINE.VOIDING.Difficulty.} OR {TOPIC.URINE.VoidingDysfunction.} OR {TOPIC.URINE.LUTS.female.} OR {TOPIC.URINE.DYSURIA.} OR {TOPIC.URINE.LUTS.antenatal.} OR {TOPIC.URINE.LUTS.Postnatal.} OR {TOPIC.URINE.STRAINING.} OR {TOPIC.URINE.UrethralStricture.} OR {TOPIC.URINE.UrethralStricture.Recurrent.} OR {TOPIC.URINE.DIVERSION*})

AND

({design.rct*} OR {design.cct*})

AND

({intvent.chem.drug*} OR {INTVENT.CHEM.DRUG.BACLOFEN.} OR {INTVENT.CHEM.DRUG.BOTULINUM TOXIN A.})

(All searches will be of the keyword field of Reference Manager 2012).

Contributions of authors

Dr ZM Yi prepared the draft text and revised the protocol following peer review. Dr. ZM Yi and Dr. RS Zhao will identify all the titles and abstracts for the review and these will be checked by other authors. All authors will be involved in writing the review.

Declarations of interest

None.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • The National Institute for Health Research (NIHR), UK.

    The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Incontinence Group.

Ancillary