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Christopher R Chapple - One of the best experts on this subject based on the ideXlab platform.
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systematic review of combination drug therapy for non neurogenic lower urinary tract symptoms
European Urology, 2019Co-Authors: Maurizio Serati, Karlerik Andersson, Roger R Dmochowski, Enrico Finazzi Agro, John Heesakkers, Valerio Iacovelli, Giacomo Novara, Vik Khullar, Christopher R ChappleAbstract:Abstract Background Several drugs are approved for the treatment of lower urinary tract symptoms (LUTS) in men, but these are mostly used by clinicians as monotherapies. The combination of different compounds, each of which targets a different aspect of LUTS, seems appealing. However, only few clinical trials have evaluated the effects of combination therapies. Objective This systematic review analyzes the efficacy and adverse events of combination therapies for male LUTS. Evidence acquisition PubMed and Cochrane databases were used to identify clinical trials and meta-analyses on male LUTS combination therapy. The search was restricted to studies of level of evidence ≥1b. A total of 49 papers published between January 1988 and March 2012 were identified. Evidence synthesis The α 1 -adrenoceptor antagonist (α 1 -blocker)/5α-reductase inhibitor (5-ARI) combination provides the most data. This combination seems to be more efficacious in terms of several outcome variables in patients whose prostate volume is between 30ml and 40ml when treatment is maintained for >1 yr; when given for 1 -blockers alone are just as effective. The combination of α 1 -blocker/5-ARI shows a slightly increased rate of adverse events. It remains unknown whether its safety and superiority over either drug as monotherapy are sustained after >6 yr. The α 1 -blocker/muscarinic receptor antagonist (Antimuscarinic) combination was most frequently assessed as an add-on therapy to already existing α 1 -blocker therapy. Inconsistent data derive from heterogeneous study populations and different study designs. Currently, the α 1 -blocker/Antimuscarinic combination appears to be a second-line add-on for patients with insufficient symptom relief after monotherapy. The combination seems to be safe in men with postvoid residual 4 mo concerning safety and efficacy of this combination. The α 1 -blocker/phosphodiesterase type 5 inhibitor combination is a new treatment option with only preliminary reports. More studies are needed before definitive conclusions can be drawn. Conclusions An α 1 -blocker/5-ARI combination is beneficial for patients whose prostate volume is between 30ml and 40ml when medical treatment is intended for >1 yr. Based on short-term follow-up studies, add-on of Antimuscarinics to α 1 -blockers is an option when postvoid residual is
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efficacy and tolerability of mirabegron compared with Antimuscarinic monotherapy or combination therapies for overactive bladder a systematic review and network meta analysis
European Urology, 2018Co-Authors: Jameel Nazir, Zalmai Hakimi, Emad Siddiqui, Con Kelleher, Richard Zur, K Maman, Samuel Aballea, Christopher R ChappleAbstract:Abstract Background Mirabegron is an established treatment alternative to Antimuscarinic therapy for patients with overactive bladder (OAB), as shown by efficacy and tolerability data from phase III trials. Objective To assess efficacy and tolerability of mirabegron 50mg versus Antimuscarinic monotherapies and combination therapies. Design, setting, and participants Systematic literature review and network meta-analysis of randomised controlled trials (2000–2017) assessing eligible treatments for OAB. Outcome measurements and statistical analysis Efficacy assessments included micturition frequency, urgency urinary incontinence, dry rate, and 50% reduction in incontinence. Tolerability assessments included dry mouth, constipation, blurred vision, and hypertension. Results and limitations A total of 64 studies ( n =46 666) were included in the network meta-analysis. Mirabegron 50mg was significantly more efficacious than placebo for all efficacy endpoints. Comparable overall efficacy was observed for mirabegron 50mg versus most active treatments, but solifenacin 10mg monotherapy and solifenacin 5mg plus mirabegron 25 or 50mg in combination were more efficacious for some/all outcomes. Mirabegron 50mg was significantly better tolerated regarding dry mouth, constipation, and urinary retention than 21/22, 9/20, and 7/10 active comparators, respectively; similar overall tolerability was observed between mirabegron 50mg and all treatments (including placebo) for the remaining endpoints. Limitations of the study included between-trial variations in the definition of certain endpoints and heterogeneity of the available data (eg, number of studies and patients assessed) for comparator treatments across different endpoints. Conclusions The relief of key OAB symptoms produced by mirabegron 50mg is significantly better than placebo, and similar to a range of common Antimuscarinics, with the benefit of significantly fewer bothersome anticholinergic side effects such as dry mouth. Combination treatment of solifenacin 5mg plus mirabegron 25 or 50mg appears to provide an efficacy benefit compared with mirabegron 50mg, with the expected side effects of individual Antimuscarinics. Patient summary This study assessed the efficacy and tolerability of different drug treatments for OAB. Mirabegron 50mg was as effective as Antimuscarinic therapy, with fewer common, bothersome side effects such as dry mouth, constipation, and urinary retention. Combination treatment of solifenacin 5mg plus mirabegron 25 or 50mg was more effective than mirabegron 50mg alone, but with more anticholinergic side effects.
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persistence and adherence with mirabegron versus Antimuscarinic agents in patients with overactive bladder a retrospective observational study in uk clinical practice
European Urology, 2017Co-Authors: Christopher R Chapple, Jameel Nazir, Zalmai Hakimi, Florent Guelfucci, Amine Khemiri, Francis Fatoye, Emad Siddiqui, Sally Bowditch, Adrian WaggAbstract:Abstract Background Persistence with Antimuscarinic therapy in overactive bladder (OAB) is poor, but may be different for mirabegron, a β 3 -adrenoceptor agonist with a different adverse event profile. Objective To compare persistence and adherence with mirabegron versus tolterodine extended release (ER) and other Antimuscarinics in routine clinical practice over a 12-mo period. Design, setting, and participants Retrospective, longitudinal, observational study of anonymised data from the UK Clinical Practice Research Datalink GOLD database. Eligibility: age ≥18 yr, ≥1 prescription for target OAB drug (between May 1, 2013 and June 29, 2014), and 12-mo continuous enrolment before and after the index prescription date. Interventions Mirabegron, darifenacin, fesoterodine, flavoxate, oxybutynin ER or immediate-release (IR), propiverine, solifenacin, tolterodine ER or IR, and trospium chloride. Outcome measurements and statistical analysis The primary endpoint was persistence (time to discontinuation). Secondary endpoints included 12-mo persistence rates and adherence (assessed using medication possession ratio, MPR). Cox proportional-hazards regression models and logistic regression models adjusted for potential confounding factors were used to compare cohorts. Analyses were repeated after 1:1 matching. Results and limitations The study population included 21996 eligible patients. In the unmatched analysis, the median time-to-discontinuation was significantly longer for mirabegron (169 d, interquartile range [IQR] 41–not reached) compared to tolterodine ER (56 d, IQR 28–254; adjusted hazard ratio [HR] 1.55, 95% confidence interval 1.41–1.71; p p Conclusions Persistence and adherence were statistically significantly greater with mirabegron than with tolterodine ER and other Antimuscarinics prescribed for OAB in the UK. Patient summary This study assessed persistence and adherence (or compliance) with medications prescribed for OAB in a large UK population. We found that patients prescribed mirabegron remained on treatment for longer and showed greater adherence than those prescribed traditional Antimuscarinics.
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the role of Antimuscarinics in the management of men with symptoms of overactive bladder associated with concomitant bladder outlet obstruction an update
European Urology, 2011Co-Authors: Anastasios Athanasopoulos, Christopher R Chapple, Steven A. Kaplan, Clare J Fowler, Christian Gratzke, Christian G Stief, Andrea TubaroAbstract:CONTEXT: This review focuses on the contemporary role of Antimuscarinics in the management of men with symptoms of bladder outlet obstruction (BOO) and concomitant overactive bladder (OAB). Safety issues of Antimuscarinics in this subpopulation of men are also reviewed. OBJECTIVE: We reviewed the current literature and performed an analysis of the efficacy, suitability, and the safety of Antimuscarinics in this subpopulation of men. EVIDENCE ACQUISITION: We performed a systematic search of Medline/PubMed, Embase, Scopus, and the Cochrane Database of Systematic Reviews for relevant articles published between 1990 and September 2010, restricted to studies in humans published in English. In addition, published abstracts presented at the annual meetings of the European Association of Urology, the American Urological Association, and the International Continence Society in the last decade (2000-2010) were hand-searched and evaluated. Each article's title and abstract were reviewed for their appropriateness and relevance to the use of Antimuscarinics in patients with BOO and concomitant OAB. Relevant articles were fully reviewed and included in the final data acquisition. EVIDENCE SYNTHESIS: Treatment options include combination treatment with α-blockers and Antimuscarinics, sequential use of α-blockers and Antimuscarinics, monotherapy with Antimuscarinics, and a combination of Antimuscarinics and 5α-reductase inhibitors. The sequential use of α-blockers and Antimuscarinics seems to be the most appropriate approach, and the use of Antimuscarinics and α-blockers appears generally to be safe and efficacious. Data are insufficient for a possible stratification of patients for a specific sequence of the drugs reviewed. CONCLUSIONS: This review infers that the existing data confirm the safety of Antimuscarinics administered for the treatment of these patients. The efficacy of Antimuscarinics has been proven in different trials regarding different storage symptom end points, but not all end points regarding OAB reached significance. All the reported trials are of short duration (4-12 wk) and include only men with low postvoid residual urine volumes at baseline (<200ml). Overall, the addition of an Antimuscarinic to the treatment of a patient with BOO and concomitant OAB seems to offer an amelioration of the symptoms and a moderate improvement in quality of life.
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Antimuscarinics in men with lower urinary tract symptoms suggestive of bladder outlet obstruction due to benign prostatic hyperplasia
Current Opinion in Urology, 2010Co-Authors: Christopher R ChappleAbstract:PURPOSE OF REVIEW: This review will provide an update on the use of Antimuscarinics, in combination with an alpha-blocker, in men with an overactive bladder and summarize the efficacy and safety of these drugs in this patient population. RECENT FINDINGS: Studies have included a number of Antimuscarinic agents (tolterodine, oxybutynin, propiverine, and solifenacin), with or without an alpha-blocker. These studies suggest that in men with persistent storage symptoms (overactive bladder symptoms), clinically meaningful improvements can be achieved by addition of an Antimuscarinic therapy to an alpha-blocker. Monotherapy with an Antimuscarinic therapy alone in this patient group has proven to be disappointing. Voiding difficulty and acute urinary retention are infrequently reported across all studies, but several trials demonstrated an increase in postvoid residual volume with anticholinergic therapy. It must, however, be borne in mind that reported trials are of short duration (6-12 weeks) and include only men with low postvoid residual volumes at baseline, and the results are, therefore, difficult to unreservedly extrapolate to real-life clinical practice. SUMMARY: In a situation in which there are persistent urinary storage symptoms (overactive bladder) following therapy with an alpha-blocker, the addition of an Antimuscarinic therapy is worth considering. A postvoid residual volume should be measured prior to commencing Antimuscarinic therapy to rule out baseline retention suggestive of poor detrusor function, and patients should be kept under careful review, particularly, in the early stages of having commenced therapy.
Karlerik Andersson - One of the best experts on this subject based on the ideXlab platform.
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systematic review of combination drug therapy for non neurogenic lower urinary tract symptoms
European Urology, 2019Co-Authors: Maurizio Serati, Karlerik Andersson, Roger R Dmochowski, Enrico Finazzi Agro, John Heesakkers, Valerio Iacovelli, Giacomo Novara, Vik Khullar, Christopher R ChappleAbstract:Abstract Background Several drugs are approved for the treatment of lower urinary tract symptoms (LUTS) in men, but these are mostly used by clinicians as monotherapies. The combination of different compounds, each of which targets a different aspect of LUTS, seems appealing. However, only few clinical trials have evaluated the effects of combination therapies. Objective This systematic review analyzes the efficacy and adverse events of combination therapies for male LUTS. Evidence acquisition PubMed and Cochrane databases were used to identify clinical trials and meta-analyses on male LUTS combination therapy. The search was restricted to studies of level of evidence ≥1b. A total of 49 papers published between January 1988 and March 2012 were identified. Evidence synthesis The α 1 -adrenoceptor antagonist (α 1 -blocker)/5α-reductase inhibitor (5-ARI) combination provides the most data. This combination seems to be more efficacious in terms of several outcome variables in patients whose prostate volume is between 30ml and 40ml when treatment is maintained for >1 yr; when given for 1 -blockers alone are just as effective. The combination of α 1 -blocker/5-ARI shows a slightly increased rate of adverse events. It remains unknown whether its safety and superiority over either drug as monotherapy are sustained after >6 yr. The α 1 -blocker/muscarinic receptor antagonist (Antimuscarinic) combination was most frequently assessed as an add-on therapy to already existing α 1 -blocker therapy. Inconsistent data derive from heterogeneous study populations and different study designs. Currently, the α 1 -blocker/Antimuscarinic combination appears to be a second-line add-on for patients with insufficient symptom relief after monotherapy. The combination seems to be safe in men with postvoid residual 4 mo concerning safety and efficacy of this combination. The α 1 -blocker/phosphodiesterase type 5 inhibitor combination is a new treatment option with only preliminary reports. More studies are needed before definitive conclusions can be drawn. Conclusions An α 1 -blocker/5-ARI combination is beneficial for patients whose prostate volume is between 30ml and 40ml when medical treatment is intended for >1 yr. Based on short-term follow-up studies, add-on of Antimuscarinics to α 1 -blockers is an option when postvoid residual is
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The efficacy of mirabegron in the treatment of urgency and the potential utility of combination therapy
Therapeutic Advances in Urology, 2018Co-Authors: Karlerik Andersson, Emad Siddiqui, Nurul Choudhury, Jean-nicolas Cornu, Moses Huang, Cees Korstanje, Philip Van KerrebroeckAbstract:Urgency is the prevalent and most bothersome symptom of overactive bladder (OAB) and the treatment of urgency is the primary objective in the management of OAB. Urgency has a major impact on other symptoms of OAB and culminates in an increased frequency of micturition and reduced volume voided, which may contribute to shorter intervals between the need to void. Antimuscarinic agents and mirabegron, a β3-adrenoceptor agonist, constitute the main oral pharmacotherapeutic options for the treatment of urgency and other OAB symptoms. The reduction of urgency and other OAB symptoms significantly improve health-related quality of life. This review will explore the distinct mechanisms of action and effects of Antimuscarinic agents and mirabegron, in relation to their effect on the pathophysiology of urgency. The review will also provide an overview of the various validated measurements of urgency and the numerous clinical trials regarding Antimuscarinic agent monotherapy, mirabegron monotherapy, or combination treatment with mirabegron added on to the Antimuscarinic agent solifenacin. A narrative review of the literature relating to pathophysiology of urgency, the validated measurements of urgency, and clinical trials relating to the pharmacological treatment of urgency. Antimuscarinic agent monotherapy, mirabegron monotherapy, or combination treatment with mirabegron added on to the Antimuscarinic agent solifenacin statistically significantly reduce the symptoms of urgency compared with placebo. Combination therapy with mirabegron added on to solifenacin also statistically significantly reduces the symptoms of severe urgency compared with Antimuscarinic agent monotherapy. A critique of the clinical benefits of combination therapy is also provided. Combination therapy provides an alternative treatment in patients with OAB that includes urgency who respond poorly to first-line monotherapy and who may otherwise often move on to more invasive treatments.
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cardiac effects of muscarinic receptor antagonists used for voiding dysfunction
British Journal of Clinical Pharmacology, 2011Co-Authors: Karlerik Andersson, Lysanne Campeau, Brian OlshanskyAbstract:Antimuscarinic agents are the main drugs used to treat patients with the overactive bladder (OAB) syndrome, defined as urgency, with or without urgency incontinence, usually with increased daytime frequency and nocturia. Since the treatment is not curative and since OAB is a chronic disease, treatment may be life-long. Antimuscarinics are generally considered to be ‘safe’ drugs, but among the more serious concerns related to their use is the risk of cardiac adverse effects, particularly increases in heart rate (HR) and QT prolongation and induction of polymorphic ventricular tachycardia (torsade de pointes). An elevated resting HR has been linked to overall increased morbidity and mortality, particularly in patients with cardiovascular diseases. QT prolongation and its consequences are not related to blockade of muscarinic receptors, but rather linked to inhibition of the hERG potassium channel in the heart. However, experience with terodiline, an Antimuscarinic drug causing torsade de pointes in patients, has placed the whole drug class under scrutiny. The potential of the different Antimuscarinic agents to increase HR and/or prolong the QT time has not been extensively explored for all agents in clinical use. Differences between drugs cannot be excluded, but risk assessments based on available evidence are not possible.
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Antimuscarinic Mechanisms and the Overactive Detrusor: An Update
European urology, 2010Co-Authors: Karlerik AnderssonAbstract:Abstract Context Antimuscarinics are the drugs of choice for the treatment of detrusor overactivity (DO) and overactive bladder (OAB) syndrome. However, the mechanisms for their beneficial effects have not yet been definitely established. Objective Literature available on the pathophysiologic aspects of storage symptoms and of Antimuscarinic actions on the bladder was reviewed. Evidence acquisition Medline was searched for the period ending October 2010 and included studies on human and animal tissues and animal models. Clinical studies exploring mechanisms involved in the effects of Antimuscarinics were included. Searches were limited to the English language. Evidence synthesis Evidence for release of acetylcholine (ACh) from non-neuronal as well as neuronal sources during bladder filling has been demonstrated in isolated animal bladders as well as the human bladder. Urothelially derived ACh, probably via release of adenosine triphosphate, may stimulate afferent activity ("afferent noise") from the bladder contributing to OAB and DO. Afferent noise may also be generated by local ACh release within the detrusor muscle. This afferent activity can be inhibited by Antimuscarinics at the low concentrations obtained with doses recommended for clinical use in OAB/DO. Within this therapeutic window, Antimuscarinics may decrease OAB symptoms and DO without affecting the voiding contraction. Changes in muscarinic receptor functions have been demonstrated with aging and in different disorders associated with OAB/DO. Conclusions ACh, derived from non-neuronal as well as neuronal sources and during bladder filling, directly or indirectly stimulates afferent activity from the bladder, contributing to OAB and DO. By inhibiting this effect, Antimuscarinics may decrease OAB symptoms and DO without affecting the voiding contraction. Even if changes in muscarinic receptor functions may occur with aging and in different disorders associated with OAB/DO, such changes have not been shown convincingly to modify the beneficial effect of Antimuscarinics in OAB/DO.
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muscarinic receptor antagonists for overactive bladder
BJUI, 2007Co-Authors: Paul Abrams, Karlerik AnderssonAbstract:From time to time we publish a full review of drugs that are available for the treatment of common conditions. In this issue, the review is written by two of the leading authorities in the world, Paul Abrams and Karl-Erik Andersson, on the topic of overactive bladder and Antimuscarinic agents. This in-depth review covers the entire range of questions that might be asked about this common area of interest. Overactive bladder (OAB) is a syndrome characterized by urinary urgency, with or without urgency urinary incontinence, usually with frequency and nocturia. OAB symptoms are often associated with detrusor overactivity (DO). Like OAB symptoms, the prevalence of DO increases with age and can have a neurogenic and/or myogenic aetiology. Bladder outlet obstruction can be a contributing factor in DO, possibly through cholinergic denervation of the detrusor and supersensitivity of muscarinic receptors to acetylcholine, although the prevalence of OAB is similar in men and women across age groups. Acetylcholine is the primary contractile neurotransmitter in the human detrusor, and Antimuscarinics exert their effects on OAB/DO by inhibiting the binding of acetylcholine at muscarinic receptors M2 and M3 on detrusor smooth muscle cells and other structures within the bladder wall. Worldwide, there are six Antimuscarinic drugs currently marketed for the treatment of OAB: oxybutynin, tolterodine, propiverine, trospium, darifenacin, and solifenacin. Each has demonstrated efficacy for the treatment of OAB symptoms, but their pharmacokinetic and adverse event profiles differ somewhat due to structural differences (tertiary vs quaternary amines), muscarinic receptor subtype selectivities, and organ selectivities. Antimuscarinics are generally well tolerated, even in special populations (e.g. men with bladder outlet obstruction, elderly patients, children). The most frequently reported adverse events in clinical studies of Antimuscarinics are dry mouth, constipation, headache, and blurred vision; few patients withdraw from clinical trials because of adverse events. Development of an Antimuscarinic with functional selectivity for the bladder would reduce the occurrence of Antimuscarinic adverse events. The therapeutic potential of several other agents, such as α3-adrenoceptor agonists, purinergic receptor antagonists, phosphodiesterase inhibitors, neurokinin-1 receptor antagonists, opioids, and Rho-kinase inhibitors, is also under investigation for the treatment of OAB.
Adrian Wagg - One of the best experts on this subject based on the ideXlab platform.
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persistence and adherence with mirabegron versus Antimuscarinic agents in patients with overactive bladder a retrospective observational study in uk clinical practice
European Urology, 2017Co-Authors: Christopher R Chapple, Jameel Nazir, Zalmai Hakimi, Florent Guelfucci, Amine Khemiri, Francis Fatoye, Emad Siddiqui, Sally Bowditch, Adrian WaggAbstract:Abstract Background Persistence with Antimuscarinic therapy in overactive bladder (OAB) is poor, but may be different for mirabegron, a β 3 -adrenoceptor agonist with a different adverse event profile. Objective To compare persistence and adherence with mirabegron versus tolterodine extended release (ER) and other Antimuscarinics in routine clinical practice over a 12-mo period. Design, setting, and participants Retrospective, longitudinal, observational study of anonymised data from the UK Clinical Practice Research Datalink GOLD database. Eligibility: age ≥18 yr, ≥1 prescription for target OAB drug (between May 1, 2013 and June 29, 2014), and 12-mo continuous enrolment before and after the index prescription date. Interventions Mirabegron, darifenacin, fesoterodine, flavoxate, oxybutynin ER or immediate-release (IR), propiverine, solifenacin, tolterodine ER or IR, and trospium chloride. Outcome measurements and statistical analysis The primary endpoint was persistence (time to discontinuation). Secondary endpoints included 12-mo persistence rates and adherence (assessed using medication possession ratio, MPR). Cox proportional-hazards regression models and logistic regression models adjusted for potential confounding factors were used to compare cohorts. Analyses were repeated after 1:1 matching. Results and limitations The study population included 21996 eligible patients. In the unmatched analysis, the median time-to-discontinuation was significantly longer for mirabegron (169 d, interquartile range [IQR] 41–not reached) compared to tolterodine ER (56 d, IQR 28–254; adjusted hazard ratio [HR] 1.55, 95% confidence interval 1.41–1.71; p p Conclusions Persistence and adherence were statistically significantly greater with mirabegron than with tolterodine ER and other Antimuscarinics prescribed for OAB in the UK. Patient summary This study assessed persistence and adherence (or compliance) with medications prescribed for OAB in a large UK population. We found that patients prescribed mirabegron remained on treatment for longer and showed greater adherence than those prescribed traditional Antimuscarinics.
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Oral pharmacotherapy for overactive bladder in older patients: mirabegron as a potential alternative to Antimuscarinics.
Current medical research and opinion, 2016Co-Authors: Adrian Wagg, Emad Siddiqui, Con Kelleher, Victor W. Nitti, David Castro-diaz, Todd BernerAbstract:AbstractObjective Overactive bladder (OAB) is a particular challenge to treat in older adults with co-morbid conditions taking multiple medications. Antimuscarinics (e.g., solifenacin, fesoterodine) and β3-adrenergic receptor agonists (mirabegron) are similarly efficacious; however, Antimuscarinics may be associated with side effects that result in poor persistence and contribute to anticholinergic burden, particularly in those taking other medications with anticholinergic properties. With a mechanism of action distinct from Antimuscarinics, mirabegron has a different tolerability profile and does not contribute to anticholinergic burden. The objective of this review was to compare and contrast the tolerability profiles of Antimuscarinics and mirabegron in older patients to inform practice.Methods Prospective trials or retrospective subgroup analyses of Antimuscarinics for the treatment of OAB in older patients were identified through a search of PubMed. Tolerability data and results of subgroup analyses ...
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persistence and adherence with the new beta 3 receptor agonist mirabegron versus Antimuscarinics in overactive bladder early experience in canada
Cuaj-canadian Urological Association Journal, 2015Co-Authors: Adrian Wagg, Billy Franks, Barbara Ramos, Todd BernerAbstract:Introduction: Antimuscarinics are the principal pharmacological treatment for overactive bladder (OAB), but frequently give rise to anticholinergic side effects, such as dry mouth, a factor leading to poor persistence. The s3-adrenoceptor agonist mirabegron is devoid of significant anticholinergic activity, while being effective in OAB. We evaluated persistence and adherence with mirabegron versus Antimuscarinics over 12 months. Methods: We obtained retrospective claims from a Canadian Private Drug Plan database for patients 18 years old and over, with a first claim for mirabegron or Antimuscarinics during a 6-month index period (April–September 2013). A 6-month look-back identified those with no prior claims for OAB medication (treatmentnaive) or ≥1 prior OAB drug (treatment-experienced). Time to end of persistence (≥30 day therapy gap or switch of therapy) was evaluated over 12 months; adherence with medication (medication possession ratio) was also measured. Results: Persistence data from 19 485 patients (74% female, 92% naive, 19.9% aged ≥65 years) showed that for experienced patients the median number of days on mirabegron was 299 days, compared with a range of 96 to 242 days for the different Antimuscarinics; for naive patients, it was 196 versus 70 to 100 days, respectively. Persistence at 12 months was for mirabegron 39% versus 14% to 35% for Antimuscarinics, (experienced) and 30% mirabegron versus 14% to 21% Antimuscarinics, (naive). Patients taking mirabegron demonstrated statistically significantly greater adherence than those taking Antimuscarinics. Conclusion: Patients who received mirabegron remained longer on treatment than those treated with Antimuscarinics, and had higher 12-month persistence and adherence rates.
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Review of the Efficacy and Safety of Fesoterodine for Treating Overactive Bladder and Urgency Urinary Incontinence in Elderly Patients
Drugs & Aging, 2015Co-Authors: Adrian Wagg, Matthias Oelke, David Scholfield, Javier C. Angulo, Daniel ArumiAbstract:Overactive bladder (OAB) is a common condition, with prevalence rates increasing with advancing age. Symptoms of OAB, including urgency urinary incontinence (UUI), are associated with various co-morbidities in elderly individuals (e.g., falls and fractures, functional impairment, and depression). The current mainstay of pharmacological therapy for OAB is Antimuscarinic agents. Until recently, few studies had specifically evaluated the efficacy and safety of Antimuscarinics in the treatment of OAB symptoms in elderly patients. This review summarises available evidence from the medical literature on the efficacy and safety of fesoterodine in elderly patients with OAB symptoms, including UUI. The data from unique placebo-controlled fesoterodine trials of elderly and vulnerable elderly patients, together with age-stratified data from post hoc analyses of fesoterodine trials, demonstrate that treatment with fesoterodine 4 or 8 mg results in statistically and clinically significant improvements in OAB symptoms and patient-reported outcomes in many elderly patients. The data indicate that the efficacy of fesoterodine in elderly patients is comparable with that in younger patients. Fesoterodine is generally well tolerated in elderly and vulnerable elderly patients, with low rates of urinary retention and little evidence of central nervous system events or impaired cognition. The data support a favourable benefit-to-risk ratio for fesoterodine in elderly and medically complex vulnerable elderly patients with OAB.
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are we shortchanging frail older people when it comes to the pharmacological treatment of urgency urinary incontinence
International Journal of Clinical Practice, 2014Co-Authors: William Gibson, Anastasios Athanasopoulos, Howard B Goldman, H Madersbacher, Diane K Newman, J Spinks, J J Wyndaele, Adrian WaggAbstract:SUMMARY Overactive bladder and urgency incontinence are common and distressing conditions in older people, for which the first-line pharmacological treatment is a bladder Antimuscarinic agent. Of these, oxybutynin is often recommended in guidelines, but is associated with a higher incidence of adverse drug effects, and in particular has been suggested to have deleterious cognitive effects. Despite this, guidelines often suggest oxybutynin as first-line treatment, and insurance based healthcare systems often require oxybutynin to be used as a first-line therapy and fail before reimbursement for the cost of newer anticholinergics is authorised. We reviewed the literature of bladder Antimuscarinics in older adults, using the headings overactive bladder, urinary frequency, urgency, urge, oxybutynin, Antimuscarinic, older, older people, and frail. In general, oxybutynin had a similar efficacy to other anticholinergic drugs, but a higher incidence of adverse drug events, in particular significant yet unnoticed cognitive impairment. We conclude that oxybutynin should not be used in frail older people. Review criteria Theinformationconsideredinthereviewwasgathered with a literature search using the headings overactive bladder, urinary frequency, urgency, urge, oxybutynin, Antimuscarinic, older, older people and frail. These were manually reviewed for relevant articles, specifically those relating to overactive bladder and its treatment in older people, and to the pharmacology, efficacy and adverse effect profile of oxybutynin. Message for the clinic Although commonly prescribed and recommended in guidelines, oxybutynin is associated with significantly worse adverse effects than other, more specific Antimuscarinics, and its use in the frail elderly should be avoided.
Emad Siddiqui - One of the best experts on this subject based on the ideXlab platform.
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efficacy and tolerability of mirabegron compared with Antimuscarinic monotherapy or combination therapies for overactive bladder a systematic review and network meta analysis
European Urology, 2018Co-Authors: Jameel Nazir, Zalmai Hakimi, Emad Siddiqui, Con Kelleher, Richard Zur, K Maman, Samuel Aballea, Christopher R ChappleAbstract:Abstract Background Mirabegron is an established treatment alternative to Antimuscarinic therapy for patients with overactive bladder (OAB), as shown by efficacy and tolerability data from phase III trials. Objective To assess efficacy and tolerability of mirabegron 50mg versus Antimuscarinic monotherapies and combination therapies. Design, setting, and participants Systematic literature review and network meta-analysis of randomised controlled trials (2000–2017) assessing eligible treatments for OAB. Outcome measurements and statistical analysis Efficacy assessments included micturition frequency, urgency urinary incontinence, dry rate, and 50% reduction in incontinence. Tolerability assessments included dry mouth, constipation, blurred vision, and hypertension. Results and limitations A total of 64 studies ( n =46 666) were included in the network meta-analysis. Mirabegron 50mg was significantly more efficacious than placebo for all efficacy endpoints. Comparable overall efficacy was observed for mirabegron 50mg versus most active treatments, but solifenacin 10mg monotherapy and solifenacin 5mg plus mirabegron 25 or 50mg in combination were more efficacious for some/all outcomes. Mirabegron 50mg was significantly better tolerated regarding dry mouth, constipation, and urinary retention than 21/22, 9/20, and 7/10 active comparators, respectively; similar overall tolerability was observed between mirabegron 50mg and all treatments (including placebo) for the remaining endpoints. Limitations of the study included between-trial variations in the definition of certain endpoints and heterogeneity of the available data (eg, number of studies and patients assessed) for comparator treatments across different endpoints. Conclusions The relief of key OAB symptoms produced by mirabegron 50mg is significantly better than placebo, and similar to a range of common Antimuscarinics, with the benefit of significantly fewer bothersome anticholinergic side effects such as dry mouth. Combination treatment of solifenacin 5mg plus mirabegron 25 or 50mg appears to provide an efficacy benefit compared with mirabegron 50mg, with the expected side effects of individual Antimuscarinics. Patient summary This study assessed the efficacy and tolerability of different drug treatments for OAB. Mirabegron 50mg was as effective as Antimuscarinic therapy, with fewer common, bothersome side effects such as dry mouth, constipation, and urinary retention. Combination treatment of solifenacin 5mg plus mirabegron 25 or 50mg was more effective than mirabegron 50mg alone, but with more anticholinergic side effects.
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The efficacy of mirabegron in the treatment of urgency and the potential utility of combination therapy
Therapeutic Advances in Urology, 2018Co-Authors: Karlerik Andersson, Emad Siddiqui, Nurul Choudhury, Jean-nicolas Cornu, Moses Huang, Cees Korstanje, Philip Van KerrebroeckAbstract:Urgency is the prevalent and most bothersome symptom of overactive bladder (OAB) and the treatment of urgency is the primary objective in the management of OAB. Urgency has a major impact on other symptoms of OAB and culminates in an increased frequency of micturition and reduced volume voided, which may contribute to shorter intervals between the need to void. Antimuscarinic agents and mirabegron, a β3-adrenoceptor agonist, constitute the main oral pharmacotherapeutic options for the treatment of urgency and other OAB symptoms. The reduction of urgency and other OAB symptoms significantly improve health-related quality of life. This review will explore the distinct mechanisms of action and effects of Antimuscarinic agents and mirabegron, in relation to their effect on the pathophysiology of urgency. The review will also provide an overview of the various validated measurements of urgency and the numerous clinical trials regarding Antimuscarinic agent monotherapy, mirabegron monotherapy, or combination treatment with mirabegron added on to the Antimuscarinic agent solifenacin. A narrative review of the literature relating to pathophysiology of urgency, the validated measurements of urgency, and clinical trials relating to the pharmacological treatment of urgency. Antimuscarinic agent monotherapy, mirabegron monotherapy, or combination treatment with mirabegron added on to the Antimuscarinic agent solifenacin statistically significantly reduce the symptoms of urgency compared with placebo. Combination therapy with mirabegron added on to solifenacin also statistically significantly reduces the symptoms of severe urgency compared with Antimuscarinic agent monotherapy. A critique of the clinical benefits of combination therapy is also provided. Combination therapy provides an alternative treatment in patients with OAB that includes urgency who respond poorly to first-line monotherapy and who may otherwise often move on to more invasive treatments.
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persistence and adherence with mirabegron versus Antimuscarinic agents in patients with overactive bladder a retrospective observational study in uk clinical practice
European Urology, 2017Co-Authors: Christopher R Chapple, Jameel Nazir, Zalmai Hakimi, Florent Guelfucci, Amine Khemiri, Francis Fatoye, Emad Siddiqui, Sally Bowditch, Adrian WaggAbstract:Abstract Background Persistence with Antimuscarinic therapy in overactive bladder (OAB) is poor, but may be different for mirabegron, a β 3 -adrenoceptor agonist with a different adverse event profile. Objective To compare persistence and adherence with mirabegron versus tolterodine extended release (ER) and other Antimuscarinics in routine clinical practice over a 12-mo period. Design, setting, and participants Retrospective, longitudinal, observational study of anonymised data from the UK Clinical Practice Research Datalink GOLD database. Eligibility: age ≥18 yr, ≥1 prescription for target OAB drug (between May 1, 2013 and June 29, 2014), and 12-mo continuous enrolment before and after the index prescription date. Interventions Mirabegron, darifenacin, fesoterodine, flavoxate, oxybutynin ER or immediate-release (IR), propiverine, solifenacin, tolterodine ER or IR, and trospium chloride. Outcome measurements and statistical analysis The primary endpoint was persistence (time to discontinuation). Secondary endpoints included 12-mo persistence rates and adherence (assessed using medication possession ratio, MPR). Cox proportional-hazards regression models and logistic regression models adjusted for potential confounding factors were used to compare cohorts. Analyses were repeated after 1:1 matching. Results and limitations The study population included 21996 eligible patients. In the unmatched analysis, the median time-to-discontinuation was significantly longer for mirabegron (169 d, interquartile range [IQR] 41–not reached) compared to tolterodine ER (56 d, IQR 28–254; adjusted hazard ratio [HR] 1.55, 95% confidence interval 1.41–1.71; p p Conclusions Persistence and adherence were statistically significantly greater with mirabegron than with tolterodine ER and other Antimuscarinics prescribed for OAB in the UK. Patient summary This study assessed persistence and adherence (or compliance) with medications prescribed for OAB in a large UK population. We found that patients prescribed mirabegron remained on treatment for longer and showed greater adherence than those prescribed traditional Antimuscarinics.
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Oral pharmacotherapy for overactive bladder in older patients: mirabegron as a potential alternative to Antimuscarinics.
Current medical research and opinion, 2016Co-Authors: Adrian Wagg, Emad Siddiqui, Con Kelleher, Victor W. Nitti, David Castro-diaz, Todd BernerAbstract:AbstractObjective Overactive bladder (OAB) is a particular challenge to treat in older adults with co-morbid conditions taking multiple medications. Antimuscarinics (e.g., solifenacin, fesoterodine) and β3-adrenergic receptor agonists (mirabegron) are similarly efficacious; however, Antimuscarinics may be associated with side effects that result in poor persistence and contribute to anticholinergic burden, particularly in those taking other medications with anticholinergic properties. With a mechanism of action distinct from Antimuscarinics, mirabegron has a different tolerability profile and does not contribute to anticholinergic burden. The objective of this review was to compare and contrast the tolerability profiles of Antimuscarinics and mirabegron in older patients to inform practice.Methods Prospective trials or retrospective subgroup analyses of Antimuscarinics for the treatment of OAB in older patients were identified through a search of PubMed. Tolerability data and results of subgroup analyses ...
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persistence with prescribed Antimuscarinic therapy for overactive bladder a uk experience
BJUI, 2012Co-Authors: Adrian Wagg, Gerhard Compion, Amanda Fahey, Emad SiddiquiAbstract:Study Type – Therapy (prevalence) Level of Evidence 2b What's known on the subject? and What does the study add? Persistence with long-term medication in chronic diseases is typically low and that for overactive bladder medication is lower than average. Sub-optimal persistence is a major challenge for the successful management of overactive bladder. Using UK prescription data, persistence was generally low across the range of Antimuscarinics. Patients aged 60 years and above were more likely to persist with prescribed oral Antimuscarinic drugs than younger patients (40–59 years). Solifenacin was consistently associated with the highest rate of persistence compared with the other Antimuscarinics included in the study OBJECTIVES • To describe the level of persistence for patients receiving Antimuscarinics for overactive bladder (OAB) over a 12-month period based on real prescription data from the UK. • To investigate patterns of persistence with oral Antimuscarinic drugs prescribed for OAB, across different age groups. PATIENTS AND METHODS • UK prescription data from a longitudinal patient database were analysed retrospectively to assess persistence with darifenacin, flavoxate, oxybutynin (extended release [ER] and immediate release [IR]), propiverine, solifenacin, tolterodine (ER/IR) and trospium. • Data were extracted from the medical records of >1 200 000 registered patients via general practice software, and anonymized prescription data were collated for all eligible patients with documented OAB (n= 4833). • Data were collected on patients who started treatment between January 2007 and December 2007 and were collected up to December 2008, to allow each patient a full 12-month potential treatment period. Failure of persistence was declared after a gap of at least 1.5 times the length of the period of the most recent prescription. • The analysis included only patients who were new to a course of treatment (i.e. who had not been prescribed that particular treatment or dosage for at least 6 months before the study period). RESULTS • The number of patients prescribed each Antimuscarinic drug varied from 23 for darifenacin to 1758 for tolterodine ER. • The longest mean persistence was reported for solifenacin (187 days versus 77−157 days for the other treatments). • At 3 months, the proportions of patients still on their original treatment were: solifenacin 58%, darifenacin 52%, tolterodine ER 47%, propiverine 47%, tolterodine IR 46%, oxybutynin ER 44%, trospium 42%, oxybutynin IR 40%, flavoxate 28%. • At 12 months, the proportions of patients still on their original treatment were: solifenacin 35%, tolterodine ER 28%, propiverine 27%, oxybutynin ER 26%, trospium 26%, tolterodine IR 24%, oxybutynin IR 22%, darifenacin 17%, flavoxate 14%. • In a sub-analysis stratified by age, patients aged ≥60 years were more likely to persist with prescribed therapy over the 12-month period than those aged <60 years. CONCLUSIONS • Twelve months after the initial prescription, persistence rates with pharmacotherapy in the context of OAB are generally low. • Solifenacin was associated with higher levels of persistence compared with other prescribed Antimuscarinic agents. • Older people are more likely than younger patients to persist with prescribed therapy. Further studies are required to understand this finding and why patients are more likely to persist with one drug rather than another.
Alphons G.h. Kessels - One of the best experts on this subject based on the ideXlab platform.
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Adverse Event Assessment of Antimuscarinics for Treating Overactive Bladder: A Network Meta-Analytic Approach
2013Co-Authors: Thomas M. Kessler, David Lohrer, Martin Umbehr, Christoph E. Minder, Lucas M Bachmann, Holger J Schunemann, Alphons G.h. KesselsAbstract:Background: Overactive bladder (OAB) affects the lives of millions of people worldwide and Antimuscarinics are the pharmacological treatment of choice. Meta-analyses of all currently used Antimuscarinics for treating OAB found similar efficacy, making the choice dependent on their adverse event profiles. However, conventional meta-analyses often fail to quantify and compare adverse events across different drugs, dosages, formulations, and routes of administration. In addition, the assessment of the broad variety of adverse events is dissatisfying. Our aim was to compare adverse events of Antimuscarinics using a network meta-analytic approach that overcomes shortcomings of conventional analyses. Methods: Cochrane Incontinence Group Specialized Trials Register, previous systematic reviews, conference abstracts, book chapters, and reference lists of relevant articles were searched. Eligible studies included randomized controlled trials comparing at least one Antimuscarinic for treating OAB with placebo or with another Antimuscarinic, and adverse events as outcome measures. Two authors independently extracted data. A network meta-analytic approach was applied allowing for joint assessment of all adverse events of all currently used Antimuscarinics while fully maintaining randomization. Results: 69 trials enrolling 269229 patients were included. Similar overall adverse event profiles were found for darifenacin, fesoterodine, transdermal oxybutynin, propiverine, solifenacin, tolterodine, and trospium chloride but not for oxybutynin orally administered when currently used starting dosages were compared
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adverse event assessment of Antimuscarinics for treating overactive bladder a network meta analytic approach
PLOS ONE, 2011Co-Authors: Thomas M. Kessler, David Lohrer, Martin Umbehr, Christoph E. Minder, Lucas M Bachmann, Holger J Schunemann, Alphons G.h. KesselsAbstract:BACKGROUND: Overactive bladder (OAB) affects the lives of millions of people worldwide and Antimuscarinics are the pharmacological treatment of choice. Meta-analyses of all currently used Antimuscarinics for treating OAB found similar efficacy, making the choice dependent on their adverse event profiles. However, conventional meta-analyses often fail to quantify and compare adverse events across different drugs, dosages, formulations, and routes of administration. In addition, the assessment of the broad variety of adverse events is dissatisfying. Our aim was to compare adverse events of Antimuscarinics using a network meta-analytic approach that overcomes shortcomings of conventional analyses. METHODS: Cochrane Incontinence Group Specialized Trials Register, previous systematic reviews, conference abstracts, book chapters, and reference lists of relevant articles were searched. Eligible studies included randomized controlled trials comparing at least one Antimuscarinic for treating OAB with placebo or with another Antimuscarinic, and adverse events as outcome measures. Two authors independently extracted data. A network meta-analytic approach was applied allowing for joint assessment of all adverse events of all currently used Antimuscarinics while fully maintaining randomization. RESULTS: 69 trials enrolling 26'229 patients were included. Similar overall adverse event profiles were found for darifenacin, fesoterodine, transdermal oxybutynin, propiverine, solifenacin, tolterodine, and trospium chloride but not for oxybutynin orally administered when currently used starting dosages were compared. CONCLUSIONS: The proposed generally applicable transparent network meta-analytic approach summarizes adverse events in an easy to grasp way allowing straightforward benchmarking of Antimuscarinics for treating OAB in clinical practice. Most currently used Antimuscarinics seem to be equivalent first choice drugs to start the treatment of OAB except for oral oxybutynin dosages of ≥ 10 mg/d which may have more unfavorable adverse event profiles.