Lincolnshire Knowledge and Resource Service

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1 Lincolnshire Knowledge and Resource Service This search summary contains the results of a literature search undertaken by the Lincolnshire Knowledge and Resource Service librarians in; January 2012 All of the literature searches we complete are tailored to the specific needs of the individual requester. If you would like this search re-run with a different focus, or updated to accommodate papers published since the search was completed, please let us know. We hope that you find the information useful. If you would like the full text of any of the abstracts listed, please let us know. Alison Price Janet Badcock alison.price@lpct.nhs.uk janet.badcock@lpct.nhs.uk Librarians, Lincolnshire Knowledge and Resource Service NHS Lincolnshire Beech House, Waterside South Lincoln LN5 7JH 1

2 Lincolnshire Knowledge and Resource Service Please find below the results of your literature search request. If you would like the full text of any of the abstracts included, or would like a further search completed on this topic, please let us know. A feedback form is included with these search results. We would be very grateful if you had the time to complete it for us, so that we can monitor satisfaction with the service we provide. Thank you! Disclaimer Every effort has been made to ensure that this information is accurate, up-to-date, and complete. However it is possible that it is not representative of the whole body of evidence available. No responsibility can be accepted for any action taken on the basis of this information. It is the responsibility of the requester to determine the accuracy, validity and interpretation of the search results. All links from this resource are provided for information only. A link does not imply endorsement of that site and the Lincolnshire Knowledge and Resource Service does not accept responsibility for the information displayed there, or for the wording, content and accuracy of the information supplied which has been extracted in good faith from reputable sources. Lincolnshire Knowledge & Resource Service Beech House, Witham Park, Waterside South, Lincoln LN5 7JH Literature Search Results Search completion date: 2 nd February 2012 Search completed by: Jan Badcock Enquiry Details Antimuscarinic treatments for overactive bladder/ urgency Resources Searched NHS Evidence TRIP Database NICE SIGN igoogle 2

3 Opening Internet Links The links to internet sites in this document are live and can be opened by holding down the CTRL key on your keyboard while clicking on the web address with your mouse Full Text Papers Links are given to full text resources where available. For some of the papers, you will need a free NHS Athens Account. If you do not have an account you can register by following the steps at: You can then access the papers by simply entering your username and password. If you do not have easy access to the internet to gain access, please let us know and we can download the papers for you. Guidance on Searching within Online Documents Links are provided to the full text of each of these documents. Relevant extracts have been copied and pasted into these Search Results. Rather than browse through often lengthy documents, you can search for specific words and phrases as follows: Portable Document Format / pdf. / Adobe Click on the Search button (illustrated with binoculars). This will open up a search window. Type in the term you need to find and links to all of the references to that term within the document will be displayed in the window. You can jump to each reference by clicking it. You can search for more terms by pressing search again. Word documents Select Edit from the menu, the Find and type in your term in the search box which is presented. The search function will locate the first use of the term in the document. By pressing next you will jump to further references. 3

4 Guidelines NICE. Urinary Incontinence References through out document. Guidelines on Urinary Incontinence European Association of Urology 2010 References through out document. Evidence The effects of antimuscarinic treatments in overactive bladder: an update of a systematic review and meta-analysis Chapple CR, Khullar V, Gabriel Z, Muston D, Bitoun CE, Weinstein D CRD summary This review concluded that antimuscarinics were efficacious, safe, well tolerated and improved health-related quality of life. The authors' conclusion about safety and efficacy seemed reasonable and likely to be reliable, although it was unclear whether this was generalisable to all relevant populations. It was not possible to assess the reliability of their conclusions on health-related quality of life. Results of the review Eighty-three RCTs were included, 10 of which were cross-over trials. The number of participants in trials ranged from 30 to 1,593; 20 trials had fewer than 100 patients and five trials had over 1,000. Return to continence: There was a statistically significant benefit with antimuscarinics compared to placebo for most of the drug categories, although these were all based on single trials (data were available for 10 of the 15 categories). Relative risk for return to continence at end of treatment ranged from 1.3 to 3.5. No data were available on fesoterodine at any dose. There were no statistically significant differences between different antimuscarinics or doses. Number of incontinence episodes per day: There was a statistically significant benefit with antimuscarinics compared to placebo for most of the drug categories; the number of trials in each pooling ranged from one to seven (data were available for 10 of the 15 categories). Pooled mean change in number of incontinence episodes ranged from 0.4 to 1.1 per day. No data were available on trospium chloride. Based on a single study, fesoterodine 8mg was more effective than tolterodine extended release 4mg. Other outcomes: There was a statistically significant benefit with antimuscarinics compared to placebo for all or most drug categories for number of micturations per day (pooled effect ranged from 0.5 to 1.3 episodes), number of urgency episodes per day (pooled effect ranged from 0.64 to 1.56 episodes), volume voided per micturation (pooled effect ranged from 13mL to 40mL) and proportion with improved bladder condition (range from 1.49 in one trial to 1.51 in another). There was some evidence of differences between individual drugs and/or doses for all outcomes except improvement in bladder condition. 4

5 Tolerability and safety: There was a statistically significant higher risk of withdrawal due to adverse events with oxybutynin (immediate release 15mg and immediate release 7.5mg to 10mg), propiverine (extended release 20mg) and solifenacin (10mg) compared to placebo. There was evidence of some difference between individual drugs and/or doses. Most treatments had a higher risk of any adverse events than placebo (pooled RR ranged from 1.00 to 2.00), but not serious adverse events. The most common adverse events were dry mouth and pruritus Quality of life data was to be reported in a separate paper. Authors' conclusions Antimuscarinics were efficacious, safe and well tolerated treatments that improved health-related quality of life. Profiles of each drug and dosage differed and should be considered when making treatment choices. Funding Grant from Pfizer Ltd Pharmacoeconomic evaluation of antimuscarinic agents for the treatment of overactive bladder Ko Y, Malone D C, Armstrong E P The study compared different antimuscarinic agents for the treatment of overactive bladder (OAB). The antimuscarinic agents and doses compared in the analysis were: immediate-release (IR) oxybutynin, 5 mg, 3 times daily; extended-release (ER) oxybutynin, 10 mg, once daily; transdermal (TD) oxybutynin, 3.9-mg patch, every 3 to 4 days, or two patches per week; IR tolterodine, 2 mg, twice daily; ER tolterodine, 4 mg, once daily; trospium, 20 mg, twice daily; solifenacin, 5 mg, once daily; and darifenacin, 15 mg, once daily. Economic study type Cost-effectiveness analysis. 5

6 A systematic review and meta-analysis of randomized controlled trials with antimuscarinic drugs for overactive bladder Novara G, Galfano A, Secco S, D'Elia C, Cavalleri S, Ficarra V, Artibani W This review concluded that extended release anticholinergic formulations were preferred to immediate release. Dose escalation may improve the efficacy of immediate release formulations, but lead to increased adverse events. More studies were needed to determine appropriate drug therapy for first-, second- and third-line treatments. This review had some important methodological limitations and the authors conclusions may not be reliable. Authors' objectives To evaluate efficacy and safety of different doses, formulations and route of administration of the available anticholinergic drugs. Results of the review Fifty RCTs and three pooled analyses were included in the review. Most included trials had a Jadad score of 3 or more. Different doses and formulations of the same drug: Efficacy: There were no significant differences between tolterodine immediate release 1mg and tolterodine immediate release 2mg for micturitions per 24 hours, volume voided per micturition and urge urinary incontinence episodes per 24 hours. With regard to adverse events, only dry mouth was significantly more frequent in those patients taking tolterodine immediate release 2mg (OR 0.52, 95% CI to 0.72, p<0.0001). Immediate release compared to extended release formulations: Oxybutynin and tolterodine were evaluated in immediate release and extended release formulations. Patients randomised to oxybutynin immediate release were significantly more likely to experience the occurrence of any adverse event (OR 1.90, 95% CI 1.03 to 3.51, p=0.04; three trials), dry mouth (OR 1.45, 95% CI 1.02 to 2.05, p=0.04; five trials). Withdrawals due to adverse events, headache, constipation and vision abnormality were similar for both formulations. Patients randomised to tolterodine extended release formulation experienced a lower number of micturitions per 24 hours (WMD 0.34, 95% CI 0.02 to 0.66, p=0.03; two trials) and a higher volume voided per micturition (WMD -9.12, 95% CI to -4.12, p=0.0004; two trials), but a similar number of incontinence episodes and pad use per day as patients randomised to tolterodine immediate release formulation. Tolterodine extended release formulations had a significantly lower rate of dry mouth (OR 1.39, 95% CI 1.13 to 1.71, p=0.002; two trials), but a higher rate of headache (OR 0.53, 95% CI 0.34 to 0.81, p=0.004; two trials). Withdrawals due to adverse events and constipation were similar in both groups. Two trials compared propiverine hydrochloride immediate release and extended release formulations and showed similar rates of adverse events, dry mouth, constipation, headache and vision abnormality. Authors' conclusions Many of the available RCTs were of good methodological quality. Extended release formulations should be preferred to the immediate release formulations due to the more favorable profile of efficacy and adverse events. For immediate release formulations, dose escalation might yield some improvements in efficacy at the cost of a significant increase in the rate of adverse events. More clinical studies were needed to determine which of the available drugs should be used as first-, second- and third-line treatments. 6

7 The cost-effectiveness of solifenacin vs fesoterodine, oxybutynin immediaterelease, propiverine, tolterodine extended-release and tolterodine immediaterelease in the treatment of patients with overactive bladder in the UK National Health Service Cardozo L, Thorpe A, Warner J, Sidhu M CRD summary This study assessed the cost-effectiveness of solifenacin versus other antimuscarinic drugs for the treatment of patients with overactive bladder syndrome. The authors concluded that, of all the therapies considered, solifenacin provided the greatest benefit for all three outcomes, and it was most cost-effective, except compared with oxybutynin for frequency and incontinence. The methods and results were generally well reported and the results appear to be appropriate, but there were some study limitations. Type of economic evaluation Cost-utility analysis Results Urgency: Solifenacin dominated fesoterodine (4mg or 8mg) and tolterodine extended release, as it was more effective and less costly. The incremental cost-effectiveness ratio (ICER) for solifenacin (5mg or 10mg) compared with propiverine extended release was 8,087 per QALY. Oxybutynin and tolterodine immediate release were not analysed. Frequency: Solifenacin dominated fesoterodine (4mg or 8mg) and tolterodine extended release and immediate release (2mg or 4mg). The ICER for solifenacin (5mg or 10mg) compared with oxybutynin immediate release was 80,009 per QALY and compared with propiverine it was 4,457 per QALY. Incontinence: Solifenacin dominated fesoterodine (4mg or 8mg) and tolterodine extended release and immediate release (2mg or 4mg). The ICER for solifenacin (5mg or 10mg) compared with oxybutynin was 87,162 per QALY and compared with propiverine it was 2,639 per QALY. The results were robust to all the sensitivity analyses conducted. The probabilistic sensitivity analysis found that solifenacin was the most cost-effective strategy for all treatment outcomes relative to fesoterodine, propiverine, and tolterodine immediate and extended release in more than 75% of simulations. Authors' conclusions The authors concluded that, of all the therapies considered, solifenacin provided the greatest clinical benefit and associated QALYs for all three outcomes, and it was most cost-effective, except compared with oxybutynin immediate release for frequency and incontinence. 7

8 The cost-effectiveness of solifenacin vs fesoterodine, oxybutynin immediaterelease, propiverine, tolterodine extended-release and tolterodine immediaterelease in the treatment of patients with overactive bladder in the UK National Health Service Source: NHS Economic Evaluation Database 31 Aug 2011 Economic evaluation. Cardozo L, Thorpe A, Warner J, Sidhu M This is a critical structured abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn.crd summary This study assessed the cost-effectiveness of solifenacin versus other antimuscarinic drugs for the treatment of patients with overactive bladder syndrome. The authors concluded that, of all the therapies considered, solifenacin provided the greatest benefit for all three outcomes, and it was most cost-effective, except compared with oxybutynin for frequency and incontinence. The methods and results were generally well reported and the results appear to be appropriate, but there were some study limitations.indexing status Cost-effectiveness analysis of antimuscarinics in the treatment of patients with overactive bladder in Spain: a decision-tree model Arlandis-Guzman S, Errando-Smet C, Trocio J, Arumi D, Rejas J This study assessed the cost-effectiveness of fesoterodine, compared with extended release tolterodine or solifenacin, for the treatment of overactive bladder. The authors concluded that fesoterodine was a cost-effective alternative to tolterodine and solifenacin, from the perspectives of society and the health care payer in Spain. The methods were valid and transparently presented. The authors conclusions appear to be robust. Results The percentage of patients who were continent at one year was with fesoterodine, with tolterodine, and with solifenacin. The expected QALYs were with fesoterodine, with tolterodine, and with solifenacin. The costs were EUR 1,937 with fesoterodine, EUR 2,089 with tolterodine, and EUR 1,960 with solifenacin. Fesoterodine was dominant as it was more effective and less expensive than the comparators. The sensitivity analyses showed that the base case findings were robust in most scenarios. With a 12-week time horizon, fesoterodine was cost-effective, from the payer perspective, but was not cost-effective from the societal perspective, compared with solifenacin (more than EUR 200,000 per QALY). Authors' conclusions The authors concluded that, from the perspectives of society and the health care payer, fesoterodine was a cost-effective alternative to tolterodine and solifenacin for the treatment of overactive bladder in Spain. 8

9 Safety and tolerability profiles of anticholinergic agents used for the treatment of overactive bladder Original article by: MG Oefelein Reference: Drug Safety Sep 2011;34(9): Date published: 22/09/ :44 Anticholinergics are the mainstay of pharmacotherapy for overactive bladder (OAB). The anticholinergics used to treat OAB differ in their pharmacological profiles, which may affect their propensity for causing commonly observed adverse effects. The purpose of this review is to use published clinical data to evaluate the safety and tolerability of commonly prescribed anticholinergics for OAB, provide a context for safety and tolerability in terms of drug pharmacology, summarise the impact of adverse effects on adherence, and discuss the influence of study design on safety and tolerability outcomes. A MEDLINE search was conducted for the period to identify studies evaluating mechanisms of action, pharmacological profiles, safety issues and adverse events pertaining to anticholinergics used in the treatment of OAB. This review found all OAB anticholinergics are effective in reducing symptoms of OAB; however, important pharmacodynamic/pharmacokinetic differences between these agents may influence their efficacy and incidence of associated adverse effects. Because OAB is a chronic disease requiring long-term therapy, careful assessment of the pharmacological differences is needed in order to tailor therapy to the individual patient's clinical needs, and thereby maximise the chance of treatment success and long-term adherence to therapy. Management/References/ September/28/Safety-and-tolerability-profiles-ofanticholinergic-agents-used-for-the-treatment-of-overactive-bladder/?id= DTB: Update on drugs for overactive bladder syndrome This article reviews the place of newer drugs and formulations for the treatment of overactive bladder syndrome under the following headings: Background Developments in drug treatment Darifenacin Solifenacin Transdermal oxybutynin Modified-release tolterodine Modified-release propiverine Trospium chloride How do the drugs compare? Safety issues The authors conclude, On current evidence, there is little to choose between available treatments in terms of efficacy. Immediate-release oxybutynin is the least expensive product and should be tried initially, but is more likely than the other oral preparations of antimuscarinic drugs to cause unwanted effects, particularly dry mouth. If these effects are intolerable, another oral preparation should be tried, taking into consideration the wide variation in costs. Compared with the oral formulations, transdermal oxybutynin is associated with fewer antimuscarinic unwanted effects, but commonly causes application-site problems severe enough for patients to discontinue treatment. 9

10 FDA approves Antares topical oxybutynin gel for treatment of overactive bladder Source: BioSpace Date published: 09/12/ :03 Summaryby: Yuet Wan The FDA has approved Antares topical oxybutynin gel 3% for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and frequency. The gel is delivered through a metered-dose pump and applied once daily to the thigh, abdomen, upper arm or shoulder, an 84 mg (approx. 3 ml) dose delivers a consistent dose of oxybutynin through the skin over a 24-hour period. Approval is based on a 12-week, placebo controlled phase III trial evaluating an 84 mg and a 56 mg dose application of oxybutynin gel vs. placebo (the FDA approved 84 mg dose). Patients treated with 84 mg oxybutynin gel daily achieved steady state drug concentrations within three days and experienced a reduction in OAB symptoms vs. placebo, including the number of urinary incontinence episodes per week. The most frequently reported treatment-related adverse events (>3%) were dry mouth (12.1% vs. 5% placebo), application site erythema (3.7% vs. 1.0% in placebo) and application site rash (3.3% vs. 0.5% in placebo). Does prior treatment for overactive bladder affect quality of life outcomes with transdermal oxybutynin? Results from the MATRIX study R. P. Goldberg MD, MPH1 and N. V. Dahl PharmD1 Background/aims: Treatment history may impact perceived effectiveness of antimuscarinic therapy for overactive bladder (OAB). This analysis of the Multicenter Assessment of Transdermal Therapy in Overactive Bladder with Oxybutynin (MATRIX) compares quality of life (QOL) in treatment-experienced vs -naive patients. Methods: MATRIX, an open-label, multicenter prospective trial, evaluated adults with OAB treated with transdermal oxybutynin 3.9 mg/d (Oxytrol, Watson Pharma, Corona, CA) for 6 mos. Study population included 3 predefined patient groups: treatment naive (n=973), recently discontinued (therapy stopped 0-29 days prior; n=785), lapsed (no therapy 30 days; n=566). King's Health Questionnaire (KHQ) was used to evaluate QOL. P values based on ANCOVA. Results: MATRIX enrolled 2878 patients (mean age 62.5y14.8y; 87% women). At baseline, 46% had OAB symptoms 4y; 57% had prior oral OAB treatment (32% of whom with multiple drugs), predominantly extended-release tolterodine or oxybutynin. Baseline differences in impairment were seen between groups (P<.0001) in 5 of 10 KHQ domains (trend for increasing severity: naive < recently discontinued < lapsed). At study end, all KHQ domains except general health perception showed significant improvement (P<.0001). Magnitude of response was similar between groups in 6 domains, with greater improvement among lapsed and naive patients in 4 domains. Conclusions: OAB patients benefit from transdermal oxybutynin, regardless of treatment history. 10

11 Meta-analysis comparing trials of antimuscarinic medications funded by industry or not PAUL K. TULIKANGAS, AMANDA AYERS, DAVID M. O SULLIVANArticle first published online: 30 MAY 2006 BJU International Volume 98, Issue 2, pages , August 2006 Methods A Medline search was conducted from January 1966 to June 2003 to identify human clinical trials of oxybutynin and tolterodine published in English. Randomized controlled trials on subjects aged 16 years who were being treated with oxybutynin or tolterodine for OAB symptoms or DOA; 24 studies were identified. The endpoints assessed were OAB symptoms or changes in uninhibited detrusor contractions on cystometrography. The outcome variables were dichotomized as improvement or no improvement. Odds ratios and 95% confidence intervals were calculated for each study based on data derived or extracted from tables and figures. Results Meta-analysis showed no significant difference in the outcomes trails funded by industry or not. Trials were then reviewed to determine their adherence to the Consolidated Standards of Reporting Trials (CONSORT) guidelines for randomized trials. CONCLUSIONS Clinical trials are important for clinicians when selecting medical therapies. In this analysis we found no difference in outcomes when comparing studies funded by industry or not for tolterodine and oxybutynin. The quality of all trials would be improved by close adherence to the CONSORT guidelines for randomized clinical trials. Tolterodine : improving QOL in patients with overactive bladder D Clemett Inpharma, 25 Jul 1998;1147:7-8 01/01/1998 The use of the new antimuscarinic agent, tolterodine for overactive bladder was discussed at a Pharmacia and Upjohn-sponsored symposium at the 93rd Annual Meeting of the American Urological Association in San Diego, USA in May Data are presented under the headings - QOL issues, at what price?, tolterodine improves QOL, compliance not a problem, economic implications and cost effectiveness of tolterodine. Solifenacin - Verdict...review of antimuscarinic drugs for the treatment of overactive bladder syndrome...symptoms of overactive erdict/solifenacin.pdf 11

12 Benefit-risk assessment of tolterodine in the treatment of overactive bladder in adults. Garely AD, Burrows L. Drug Saf. 2004;27(13): Overactive bladder is associated with symptoms of urgency, with or without urge incontinence, usually with daytime frequency and nocturia in the absence of local pathological factors. Muscarinic receptor antagonists (antimuscarinics) are the first-line pharmacotherapy. Tolterodine, a competitive, nonselective antimuscarinic specifically developed for the treatment of overactive bladder, demonstrated tissue selectivity for the bladder over the parotid gland in an animal model. As of March 5, 2003, the immediaterelease (IR) formulation had been approved in 72 countries and the extended-release (ER) formulation had been approved in 28 countries, and tolterodine had been administered to 5 million patients. This review evaluates the benefit-risk profile of tolterodine in the treatment of adults with overactive bladder, summarising clinical trial and postmarketing surveillance data. Tolterodine has been found to significantly reduce micturition frequency, urgency perception and the number of episodes of urge incontinence and increase the volume voided per micturition. Dry mouth, an antimuscarinic class effect, is the most commonly reported adverse effect but is mostly mild to moderate in severity. Serious adverse effects are reported infrequently. Based on summary and review of postmarketing surveillance and clinical trial safety data received by the market authorization holder and contained in the Periodic Safety Update Reports for tolterodine, several monitored serious events of the gastrointestinal tract (e.g. ileus or haemorrhage), nervous system (e.g. syncope, convulsions and memory disorders) and cardiovascular system (e.g. ventricular arrhythmia, atrial fibrillation, palpitations, bradycardia, transient ischaemic attacks and hypertension) were not considered related to tolterodine. QT or corrected QT (QTc) prolongation was not observed in any of the five cases of verified ventricular arrhythmia in patients administered tolterodine; there is insufficient evidence to indicate that tolterodine causes ventricular arrhythmia or extrasystoles or any specific type of cardiac rhythm abnormality. The safety profile of tolterodine is similar in patients aged > or =65 years and in younger adults. Clinically relevant drug interactions are limited to cytochrome P450 3A4 inhibitors, such as ketoconazole, and co-administration with such agents warrants a tolterodine dosage decrease. In addition, tolterodine IR 2mg twice daily is similar in efficacy to oxybutynin IR 5mg three times daily, and tolterodine ER 4 mg once daily is similar in efficacy to oxybutynin ER 10mg once daily. Dry mouth occurred less frequently with tolterodine than oxybutynin, and moderate to severe dry mouth occurred more than three times less frequently. Based on the low frequency of adverse events, the absence of unexpected adverse events and the very low frequency of serious adverse events, we conclude that tolterodine is a well tolerated treatment for overactive bladder in adults, in whom it should be considered as first-line therapy. 12