Conservative treatment

Transcription

1 Urgency urinary incontinence (UUI)/overactive bladder (OAB) treatment includes conservative management, medication and third- line treatment. Conservative treatment Conservative management includes lifestyle interventions, behavior therapy/scheduled voiding and physical therapies. Lifestyle interventions In terms of lifestyle adjustment, there are many factors associated with UUI/OAB, including obesity, caffeine reduction and diet. Obesity has been identified as a risk factor for urinary incontinence (UI) in many epidemiological studies 1, 2. The prevalence of UUI/OAB increases proportionately with elevating body mass index. There were several research proposed on the effect of caffeine reduction on UI 3-6. They were of moderate quality and the results were inconsistent. The studies were mainly in women, so results can only be cautiously generalized to men. There were two randomized control trials (RCTs) investigating caffeine reduction. 4, 5 One RCT showed that reducing caffeine intake resulted in reducing urgency but not reducing UI. 4 However, the study was not powered for UI and compared the interventions of bladder training (BT) and caffeine reduction against BT alone. Another RCT found that reducing caffeine had no benefit for UI. 5 An uncontrolled study suggested that people with OAB and high caffeine intake were more likely to show DO on filling during conventional cystometry. 3 A further interventional study in the elderly showed borderline significance for the benefit of reducing caffeine intake on UI. 6 In a large prospective cohort study there was no evidence that caffeine reduction reduced the risk of progression of urinary incontinence over 2 years. 7 Behavior therapy/scheduled voiding Behavioral treatments are designated as a group of therapies that improve OAB symptoms by changing patient s behavior or environment. Most effective behavioral treatment programs include multiple components and are specific to the unique needs of those UUI/OAB patients and their unique living surroundings. This approach focuses on modifying bladder function by changing voiding habits, like bladder training and delayed voiding. The goals of behavior treatment are to correct voiding patterns, improve the ability to suppress urge and increase bladder capacity and continence. Two main RCTs, which compared bladder therapy with no intervention,

2 found that UI was improved, but not cured, by timed bladder voiding at intervals of between 2.5 and 4 hours. 8,9 Physical therapies The other counterpart of behavioral training focuses on the bladder outlet and pelvic floor muscle training to improve strength and control and techniques for urge suppression. Specific components of behavioral treatment can include self-monitoring (bladder diary), scheduled voiding, delayed voiding, double voiding, pelvic floor muscle training and exercise (including pelvic floor relaxation), active use of pelvic floor muscles for urethral occlusion and urge suppression (urge strategies), urge control techniques (distraction, self-assertions), normal voiding techniques, biofeedback, electrical stimulation. Behavioral therapies are most often implemented by advance practice nurses (e.g., continence nurses) or physical therapists with training in pelvic floor therapy. Medication therapy Antimuscarinic drugs (also commonly referred to as anticholinergic drugs) are currently the mainstay of treatment for UUI. They act by blocking muscarinic receptors in the bladder wall. This reduces Detrusor contractility and also alters sensation. Antimuscarinic agents differ in their pharmacological profiles, e.g. muscarinic receptor affinity and other modes of action, in their pharmacokinetic properties, e.g. lipid solubility and half-life, and in their formulation, e.g. immediate release (IR), extended release (ER) or transdermal. Efficacy evaluation The evaluation of cure or improvement of UI using oxybutynin and tolterodine IR formulations is made harder by the lack of a standard definition of improvement and the failure to use cure as a primary outcome. Meta-analysis of the published evidence is therefore not always possible. In general, these reviews noted that the treatment effect of drugs is usually small, while the treatment effect of other conservative therapies is large. An extensive review of the randomized trials that evaluated pharmacologic therapies for OAB (including trials with placebo control groups as well as trials with active treatment comparison groups) revealed no compelling evidence for differential efficacy across medications This finding is consistent with the conclusions of

3 several published systematic reviews These data were not suitable for meta-analysis due to of lack of variance information (e.g., standard deviations, variances, standard error of the mean) for outcomes in many studies. Qualitative analysis revealed, however, that for 24-hour frequency, urgency incontinence and incontinence, baseline symptom level was closely related to degree of symptom reduction across medications. Specifically, patients with more severe symptoms, on average, experienced greater symptom reductions. For urgency incontinence and total incontinence episodes, only patients with relatively low baseline symptom levels were likely to experience complete symptom relief. Due to the similar efficacy observed for all oral anti-muscarinic medications, the choice of medication for a particular patient depends on the patient s history of anti-muscarinic use, information regarding adverse events experienced The 2012 edition of these Guidelines separated out IR antimuscarinics from ER preparations. The 2012 AHRQ review did a detailed evaluation of all antimuscarinic drugs up to December 30th 2011, but did not review IR preparations separately. The IR formulation of oxybutynin is the prototype drug in the treatment of UUI. Oxybutynin IR provides maximum dosage flexibility, including an off-label on-demand use. Immediate-release drugs have a greater risk of side effects than ER formulations because of their higher plasma peak levels. A transdermal delivery system (TDS) and gel developed for oxybutynin has improved its side effect profile while still maintaining efficacy. Evidence summary (Level of evidence) Oxybutynin IR and transdermal, tolterodine IR, and propiverine IR provide a significantly better rate of cure or improvement of UI compared to placebo.(1a) Trospium IR provides a significantly better reduction in incontinence episodes than placebo. (1a) ER formulations of antimuscarinic agents are effective for improvement and cure of UUI. (1b) ER formulations of antimuscarinic agents result in higher rates of dry mouth compared to placebo. (1b) Side effects Dry mouth is the commonest side effect, though others include constipation, blurred vision, fatigue and cognitive dysfunction. When people have a dry mouth, they may be inclined to drink more, but it is not clear whether this adversely influences the effect of the drug. In the past, the impact on the patient of adverse events, patient preferences,

4 comorbidities, use of other medications and the availability of and resources to acquire specific medications. In addition, although there was no evidence of differential efficacy across medications, both qualitative analysis and meta-analysis of all randomized trial arms revealed different adverse event profiles for dry mouth and constipation.* This information may be relevant if a patient is particularly sensitive to one of these adverse events. There was no evidence that any one antimuscarinic agent improved QoL more than another agent. 76 Dry mouth is the most prevalent and most studied adverse effect of antimuscarinic agents. Good evidence indicates that, in general, ER formulations of both short-acting drugs and longer-acting drugs are associated with lower rates of dry mouth than IR preparations Oxybutynin IR showed higher rates of dry mouth than tolterodine IR and trospium IR, but lower rates of dry mouth than darifenacin, 15 mg daily Overall, oxybutynin ER has resulted in higher rates of dry mouth than tolterodine ER, but generally oxybutynin did not have higher rates for moderate or severe dry mouth. Transdermal oxybutynin was associated with a lower rate of dry mouth than oxybutynin IR and tolterodine ER, but had an overall higher rate of withdrawal due to an adverse skin reaction. 76 Solifenacin, 10 mg daily, had higher rates of dry mouth than tolterodine ER. 76 Fesoterodine, 8 mg daily, had a higher rate of dry mouth than tolterodine, 4 mg daily. 28,78 In general, discontinuation rates were similar for each treatment arm in comparative RCTs, irrespective of differences in the occurrence of dry mouth. In conclusion, there is no consistent evidence for the superiority of one antimuscarinic agent over another the size of effect. There is good evidence that ER, once daily, and transdermal preparations, are associated with lower rates of dry mouth than ER preparations, although discontinuation rates are similar. With regard to dry mouth, meta-analysis revealed that on average 6.90% of placebo patients experienced dry mouth (40 placebo arms; 95% CI: 5.6% to 8.5%). Rates of dry mouth in active drug treatment arms for the newer medications (i.e., darifenacin 9 arms, fesoterodine 11 arms, solifenacin 15 arms) and for trospium (8 arms) ranged from 20.0% to 40.0%. Within each medication, there was no clear relationship between rate and dose. Across medications, rates were statistically indistinguishable with overlapping confidence intervals and derived from relatively few trial arms for each medication; the Panel interpreted these findings as preliminary and descriptive rather than definitive until more data are available. The majority of the available studies evaluated oxybutynin (25 trial arms) and

5 tolterodine (40 trial arms). The rate of dry mouth for oxybutynin at 61.4% was statistically significantly higher (95% CI: 52.5% to 69.5%) than the 23.7% rate for tolterodine (95% CI: 20.7% to 26.9%) (p<0.001). Although there was no clear relationship with dose, there was heterogeneity within each medication based on whether the immediate release (IR) or the extended release (ER) formulation was administered (see Guideline Statement 8 below). With regard to constipation, on average 3.6% of placebo patients experienced this adverse event (36 placebo arms; 95% CI: 2.7% to 4.8%). Constipation rates in active drug treatment arms for fesoterodine (11 arms), solifenacin (15 arms), and trospium (5 arms) ranged from 7.0% to 9.0%. These rates were statistically indistinguishable with similar 95% confidence intervals spanning 5.0% to 12.0%. The constipation rate for darifenacin (9 arms), however, was significantly higher at 17.0% (95% CI: 13.0% to 21.0%). Within each medication, there was no clear relationship between rate and dose. Since these data were derived from relatively few trial arms, the Panel again interpreted them as descriptive rather than definitive until more data are available. The majority of the available studies evaluated oxybutynin (21 trial arms) and tolterodine (34 trial arms). The rate of constipation for oxybutynin was 12.1% (95% CI: 7.9% to 18.0%). The rate for tolterodine was statistically significantly lower (p<0.001) at 4.9% (95% CI: 4.1% to 5.7%). There were no differences based on dose or between the IR and ER formulations for either medication. Recommendations for antimuscarinic drugs GR Offer IR or ER formulations of antimuscarinic drugs as initial drug therapy for adults with urge urinary incontinence. (Grade A) If IR formulations of antimuscarinic drugs are unsuccessful for adults with urge urinary incontinence, offer ER formulations or longer-acting antimuscarinic agents. (Grade A) Consider using transdermal oxybutynin if oral antimuscarinic agents cannot be tolerated due to dry mouth. (Grade B) Offer and encourage early review (of efficacy and side effects) of patients on antimuscarinic medication for urge urinary incontinence (< 30 days). (Grade A) When prescribing antimuscarinic drugs to elderly patients, be aware of the risk of cognitive side effects, especially in those receiving cholinesterase inhibitors. (Grade C) Avoid using oxybutynin IR in patients who are at risk of cognitive dysfunction. (Grade A) Consider use of trospium chloride in patients known to have cognitive dysfunction. (Grade B)

6 Use antimuscarinic drugs with caution in patients with cognitive dysfunction. (Grade B) Do an objective assessment of mental function before treating patients whose cognitive function may be at risk. (Grade C) Check mental function in patients on antimuscarinic medication if they are at risk of cognitive dysfunction. (Grade C) Adrenergic drugs for UI Recently, research has focused on beta 3-adrenoceptor stimulation as a treatment of increasing detrusor relaxation and thus improving the storage of urine in the urinary bladder in the patients with UUI/OAB. Mirabegron is a beta 3 agonist available in the European countries and U.S. from Beta 3 adrenoceptors are largely expressed in the smooth muscle cells of the detrusor and their stimulation induces detrusor relaxation. Efficacy evaluation: There were three RCTs and one pooled analysis done and shown that treatment outcome of mirabegron at 3 different doses (25, 50 and 100 mg) is significantly greater reduction in incontinence episodes and daily micturition frequency than placebo group They demonstrated the statistically significant difference is only for improvement with average cure rates around 43% and 50% but not cure of UI. Another large European-Australian multi-centre, 4 arms, RCT of mirabegron 50 and 100 mg, and tolterodine ER 4 mg vs. placebo showed significant improvement in UI for mirabegron vs. placebo. Interestingly, high dosage of mirabegron 100 mg showed no higher treatment benifit compared to 50 mg. 83 Khullar et al further reported a sub-group analysis of this large population assessing the efficacy of mirabegron in patients who were treatment naïve and those who had received prior antimuscarinic therapy for UUI/OAB. They reported resembling improvements in frequency of incontinence episodes and daily micturitions in all the groups. 84 Side effects: Nitti et al reported no difference in the rate of adverse events between treatment and placebo groups in the RCTs Dry mouth: Khullar et al demontrastes the rates of dry mouth were significantly lower compared to tolterodine, and no different than placebo. 83 Cardiac arrhythmia:

7 One RCT have specifically addressed the comparative risk of QTc prolongation and showed no difference from placebo up to 100 mg dose. 85 Another RTC revealed no significant difference in rate of side effects at different doses of Mirabegron. 86 Urodynamic parameters: Nitti et al. assessed the effect of mirabegron on max flow rate and detrusor pressure at max flow in men with combined BOO and OAB. They reported that mirabegron (50 or 100 mg) showed no significant influence on these two urodynamic parameters compared to placebo. 87 Recommendation GR Mirabegron is another choice for people with urgency urinary incontinence, but report of long-term side effect is still not available. (Grade B) Third-line treatments Third-line treatments of various neuromodulation therapies require active participation by a motivated patient. Sacral neuromodulation is invasive and presents the risk of rare adverse events that may not be quickly reversible, such as infection. Treatment with intradetrusor onabotulinumtoxin A is invasive and presents risks for infection as well as increased post-void residuals and the potential need for self-catheterization, which is not quickly reversible. Additional treatments, such as various kinds of surgery, present the risks of major surgery and are irreversible. Surgery for refractory DO Intravesical injection of botulinum toxin A The Cochrane analysis, which included patients with neurogenic or idiopathic DO, reported on RCTs comparing BTX with placebo. 88 Reduction of incontinence episodes favoured BTX over placebo at both 4-6 weeks and 12 weeks. The mean difference in the reduction of incontinence episodes per day was (95% CI: to -1.01; p=0.002). The rise in PVR favored the placebo group, with a mean increase in PVR of 70.2 ml with the BTX. Up to 66% of patients achieved complete continence, with an effect lasting between 3 and 12 months. Augmentation cystoplasty The largest case series of bladder augmentation in UUI included 51 women with UUI. 89 At an average follow-up of 74.5 months, only 53% were continent and satisfied with the surgery, whereas 25% had occasional leaks and 18% continued to have disabling UUI. It is difficult to extract data on non-neurogenic patients from

8 these case series, but in general the results for patients with idiopathic DO (58%) seemed to be less satisfactory than for patients with neurogenic overactivity (90%). Urinary diversion It is rarely needed in the treatment of non-neurogenic UUI. There are no studies that have specifically examined this technique in the treatment of non-neurogenic UI.

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