Effect of norepinephrine reuptake inhibitors combined antimuscarinic agents versus monotherapy for OSA: a systematic review and meta-analysis.

STUDY OBJECTIVES: Randomized controlled trials have shown that combining norepinephrine reuptake inhibitors and antimuscarinics can ameliorate the severity of obstructive sleep apnea (OSA). This article explores whether the effectiveness and safety of combining norepinephrine reuptake inhibitors with antimuscarinic agents surpass monotherapy for treating OSA. METHODS: We searched the randomized controlled trials (RCTs) with adult patients of OSA who received combination and monotherapy in eight databases from inception until April 5, 2023, next evaluated the included studies' quality, and conducted a meta-analysis and systematic review. The primary outcome was the apnea-hypopnea index (AHI). Secondary outcome measures included loop gain, hypoxic load, oxygen desaturation index, and Vpassive, among other indicators. We assessed the quality of the studies using Cochrane Methods criteria. RESULTS: Identifying four RCTs for systematic review and two for meta-analysis. The results of the meta-analysis showed that norepinephrine reuptake inhibitors combined with antimuscarinic agents in patients with OSA prolonged total sleep time by a mean of 28.20 min [95% CI (5.78, 50.61), P = 0.01], increased sleep efficiency by 4.73% [95%CI (0.50, 8.97), P = 0.03] compared with norepinephrine reuptake inhibitors alone. Other indices and adverse events were no statistical significance. The systematic reviews revealed that norepinephrine reuptake inhibitors combined with antimuscarinics may be superior to monotherapy in improving AHI and endotypic traits. CONCLUSIONS: This article demonstrated the potential advantages of combining norepinephrine reuptake inhibitors plus antimuscarinics for treating OSA, contrasting with the norepinephrine reuptake inhibitors alone, and revealed no statistically significant safety.

The Role of Long-Acting Antimuscarinic Agents in the Treatment of Asthma.

The journey of using anticholinergics in the treatment of asthma started with anticholinergic-containing plants such as Datura stramonium and Atropa belladonna, followed by ipratropium bromide and continued with tiotropium, glycopyrronium, and umeclidinium. Although antimuscarinics were used in the maintenance treatment of asthma over a century ago, after a long time (since 2014), it has been recommended to be used as an add-on long-acting antimuscarinic agent (LAMA) therapy in the maintenance treatment of asthma. The airway tone controlled by the vagus nerve is increased in asthma. Allergens, toxins, or viruses cause airway inflammation and inflammation-related epithelial damage, increased sensory nerve stimulation, ganglionic and postganglionic acetylcholine (ACh) release by inflammatory mediators, intensification of ACh signaling at M1 and M3 muscarinic ACh receptors (mAChRs), and dysfunction of M2 mAChR. Optimal anticholinergic drug for asthma should effectively block M3 and M1 receptors, but have minimal effect on M2 receptors. Tiotropium, umeclidinium, and glycopyrronium are anticholinergic agents with this feature. Tiotropium has been used in a separate inhaler as an add-on treatment to inhaled corticosteroid (ICS)/long-acting ß2-agonist (LABA), and glycopyrronium and umeclidinium have been used in a single inhaler as a combination of ICS/LABA/LAMA in asthma in recent years. Guidelines recommend this regimen as an optimization step for patients with severe asthma before initiating any biologic or systemic corticosteroid therapy. In this review, the history of antimuscarinic agents, their effectiveness and safety in line with randomized controlled trials, and real-life studies in asthma treatment will be discussed according to the current data.

Pharmacotherapy for obstructive sleep apnea - A systematic review and meta-analysis of randomized controlled trials.

Continuous positive airway pressure is the first-line and gold-standard treatment for obstructive sleep apnea (OSA). Pharmacotherapy is not commonly used in treating OSA until recently. Combined noradrenergic and antimuscarinic agents have been clinically applied for OSA patients with variable results. This meta-analysis study aimed to investigate the efficacy of the combined regimen on OSA. A systematic literature search was performed up to November 2022 for the effects of the combined regimen on OSA. Eight randomized controlled trials were identified and systematically reviewed for meta-analysis. There were significant mean differences between OSA patients taking a combined regimen and placebo in apnea-hypopnea index (AHI) [mean difference (MD) -9.03 events/h, 95%CI (-16.22, -1.83 events/h; P = 0.01] and lowest oxygen saturation [MD 5.61%, 95% CI % (3.43, 7.80); P < 0.01]. Meta-regression showed that a higher proportion of male participants was associated with a greater reduction of AHI (p = 0.04). This study showed a positive but modest effect of pharmacotherapy in the reduction of OSA severity. The combination drugs are most applicable to male OSA patients based on their efficacy and pharmacological susceptibility. Pharmacotherapy may be applied as an alternative, adjunctive or synergistic treatment under careful consideration of its side effects.

Pharmacological interventions for reducing catheter-related bladder discomfort in patients undergoing elective surgeries under general anaesthesia: A systematic review and meta-analysis.

Background and Aims: Catheter-related bladder discomfort (CRBD) is identified as a major concern after surgery as it can lead to increased morbidity and prolonged hospital stay. A suitable agent to prevent and treat postoperative CRBD is not yet established, and the literature is scarce in this regard. So, we aimed to find the efficacy of various drugs in preventing CRBD after elective surgery. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed for the study, and electronic databases like PubMed Central, Cochrane database and Embase were searched. The methodological quality of selected studies was assessed by the Cochrane Collaboration risk of bias tool. Review Manager 5.4.1 was used for statistical analysis. Results: The meta-analysis revealed that antimuscarinic agents were able to lower the incidence of CRBD significantly at 0 hour, 1 hour, 2 hours and 6 hours (P < 0.01) after the surgery. Tramadol was effective at 1 hour, 2 hours and 6 hours postoperatively (P < 0.01), whereas ketamine was effective at 2 and 6 hours (P < 0.01) postoperatively. Antiepileptic drugs (pregabalin and gabapentin) were able to lower the incidence of CRBD at 0 hour (P < 0.01), 1 hour (P < 0.05), 2 hours (P < 0.05) and 6 hours (P < 0.01) postoperatively while dexmedetomidine at 0 hour (P < 0.01) and 2 hours (P < 0.01) after the surgery. Injections paracetamol, amikacin and diphenhydramine were also shown to reduce the incidence of CRBD in separate randomised controlled trials. Conclusion: The current meta-analysis showed that antimuscarinic agents, tramadol, pregabalin, gabapentin, paracetamol and dexmedetomidine are effective in significantly reducing the incidence of postoperative CRBD.

COPD and glycopyrronium responsiveness assessment: An appraisal.

Clinical Trial Registration: ECR/159/Inst/WB/2013/RR-20. Background: Glycopyrronium bromide (a long-acting antimuscarinic agent: LAMA) appears pharmacokinetically suitable for testing bronchodilator responsiveness as salbutamol (short-acting ß2-agonist: SABA). Exploring the feasibility, acceptability, degree of reversibility with glycopyrronium, and its comparison with that of salbutamol may be intriguing. Methods: New, consecutive, and willing outpatient attendees in the same season of the two consecutive years with chronic obstructive pulmonary disease (FEV1/FVC <0.07; FEV1 <80% of predicted) were subjected to serial responsiveness with inhalation of salbutamol first followed by 50 µg dry powder glycopyrronium [Salbutamol- Glycopyrronium] (phase-1) in the first year and glycopyrronium followed by salbutamol [Glycopyrronium- Salbutamol] (phase-2) in the following year. We looked for the acceptability, adverse reactions, and degree of changes in FEV1, FVC, FEV1/FVC, and FEF25-75 with comparison between the two groups. Results: The [Salbutamol- Glycopyrronium] group (n = 86) were similar in age, body mass index, and FEV1 to the [Glycopyrronium- Salbutamol] group (n = 88). Both the agents could make a significant (P <.0001) improvement in the parameters independently or as add-on when used serially in alternate orders. The intergroup difference at no stage was significant. The sensitive patients to salbutamol (n = 48), glycopyrronium (n = 44), and both (n = 12) have improvement of 165, 189, and 297 mL while a both-insensitive group (n = 70) had barely 44 mL of improvement. The protocol was universally accepted without any adverse events. Conclusion: Serial testing of salbutamol and glycopyrronium responsiveness in alternate orders provides an insight regarding the independent and the add-on effects of these two agents. About 40% of our chronic obstructive pulmonary disease patients had no clinically appreciable difference in FEV1 with the salbutamol + glycopyrronium combination inhalation.

TReating Incontinence for Underlying Mental and Physical Health (TRIUMPH): a study protocol for a multicenter, double-blinded, randomized, 3-arm trial to evaluate the multisystem effects of pharmacologic treatment strategies for urgency-predominant urinary incontinence in ambulatory older women.

BACKGROUND: Urgency-type urinary incontinence affects one in four older community-dwelling women and overlaps with other common aging-associated health syndromes such as cognitive impairment, physical mobility impairment, and depression. Observational studies have raised concern about potentially higher rates of delirium and dementia in older adults taking anticholinergic bladder medications, but few prospective data are available to evaluate the effects of these and other pharmacologic treatments for urgency incontinence on cognition and other multisystem functional domains important to older women. METHODS: The TRIUMPH study is a randomized, double-blinded, 3-arm, parallel-group trial comparing the multisystem effects of anticholinergic versus beta-3-adrenergic agonist bladder therapy and versus no active bladder anti-spasmodic pharmacotherapy in older women with urgency incontinence. Women aged 60 years and older (target N = 270) who have chronic urgency-predominant urinary incontinence and either normal or mildly impaired cognition at baseline are recruited from the community by investigators based in northern California, USA. Participants are randomized in equal ratios to take identically encapsulated oral anticholinergic bladder therapy (in the form of tolterodine 2 mg extended release [ER]), oral beta-3 adrenergic agonist bladder therapy (mirabegron 25 mg ER), or placebo daily for 24 weeks, with the option of participant-directed dose titration (to tolterodine 4 mg ER, mirabegron 50 mg ER, or matching placebo daily). Participants also receive patient-oriented information and instructions about practicing first-line behavioral management strategies for incontinence. The primary outcome is change in composite cognitive function over 24 weeks assessed by a comprehensive battery of cognitive tests, with a secondary exploration of the persistence of change at 36 weeks. Secondary outcomes include changes over 24 and 36 weeks in domain-specific cognitive function; frequency, severity, and impact of urgency-associated urinary symptoms; physical function and balance; sleep quality and daytime sleepiness; psychological function; and bowel function. DISCUSSION: The TRIUMPH trial addresses the need for rigorous evidence to guide counseling and decision-making for older women who are weighing the potential multisystem benefits and risks of pharmacologic treatments for urgency incontinence in order to preserve their day-to-day functioning, quality of life, and independence in older age. TRIAL REGISTRATION: ClinicalTrials.gov NCT05362292. Registered on May 5, 2022.

Cost-effectiveness evaluation of mirabegron versus anti-muscarinics and third-line therapies: a systematic review.

BACKGROUND: Overactive bladder (OAB) is defined as urinary urgency, usually with urinary frequency and nocturia. . The current treatment for OAB includes conservative management, surgery, and pharmacotherapy. Mirabegron is a new drug acting by the ß3-adrenoceptor agonism. This study aimed to review the cost-effectiveness of mirabegron in the treatment of OAB. AREAS COVERED: We searched published articles in electronic search databases. Ten studies were included in the qualitative analysis. Various antimuscarinics, including oxybutynin, fesoterodine, tolterodine, darifenacin, and trospium were compared with mirabegron. The results were evaluated and compared according to the quality-adjusted life-years (QALY), cost/year, and incremental cost-effectiveness ratio (ICER). Of the ten studies in only three, mirabegron was not a cost-effective strategy. In seven cases, mirabegron was cost-effective. EXPERT OPINION: The cost-effectiveness of mirabegron was variable in different regions; however, most of the studies show the cost-effectiveness of mirabegron. Our study illustrates that mirabegron's ICER in comparison with its comparators is below the willingness to pay threshold even in the countries with low GDP/Capita. Our proposal for future economic studies for OAB pharmacotherapy is to compare different doses, formulations, and administration forms in a real-world context.

Choosing the Most Efficacious and Safe Oral Treatment for Idiopathic Overactive Bladder: A Systematic Review and Network Meta-analysis.

CONTEXT: The choice of the most efficacious drug for patients with idiopathic overactive bladder (IOAB) remains challenging. OBJECTIVE: The aim of this network meta-analysis was to determine the most efficacious oral antimuscarinic or ß-adrenoceptor agonist accounting for adverse events for the management of IOAB. EVIDENCE ACQUISITION: A comprehensive electronic search was done in MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, and Ovid for studies in any language in February 2021 considering the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. We included all randomized controlled trials assessing oral antimuscarinics or ß-adrenoceptor agonists for the treatment of IOAB. We determined the effect of specific bothersome symptoms separately. EVIDENCE SYNTHESIS: Fifty-four articles were included in our analysis. The most efficacious agents considering the evaluated outcomes were oxybutynin 15 mg/d in reducing incontinence episodes, imidafenacin 0.5 mg/d together with solifenacin 10 and 5 mg/d in reducing micturition episodes, fesoterodine 4 and 8 mg/d as well as solifenacin 10 mg/d in reducing urgency episodes, imidafenacin 0.5 mg/d and solifenacin 10 mg/d in reducing urgency urinary incontinence episodes, and solifenacin 10 mg/d, vibegron 50 mg/d, and fesoterodine 8 mg/d in improving the voided volume. Gastrointestinal problems, especially due to antimuscarinic agents, were the most prevalent adverse events. CONCLUSIONS: Taken together, there is only minimal difference between the efficacy of oral antimuscarinics and that of ß-adrenoceptor agonists. Although finding the best medication for all is impossible, finding the best treatment for every individual patient can be done by considering the efficacy of a medicine for the most bothersome symptom(s) in balance with drug-specific adverse events. PATIENT SUMMARY: This study aimed to find the most efficient oral medication to treat overactive bladder, taking into consideration the adverse events. Based on our study, there is a minimal difference in the efficacy between the two major drug classes used to treat overactive bladder. Gastrointestinal problems were the most common adverse events in medical treatment of overactive bladder. Selection of the best treatment is possible through shared decision-making between the doctor and the patient based on the patient's most bothersome symptom. We provide a framework for physicians to facilitate shared decision-making with each individual patient.

New Treatments for Asthma.

Asthma is a complex, heterogeneous chronic airway disease with high prevalence of uncontrolled disease. New therapies, including biologics, are now available to treat T2 high asthma. Treatment of T2 low asthma remains a challenge. Asthma guidelines need be to updated to incorporate new therapeutics.

Efficacy of trospium for prevention of catheter-related bladder discomfort: a prospective, randomized, placebo-controlled, double-blind study.

BACKGROUND: Catheter-related bladder discomfort (CRBD) is a frequent complaint after awakening from anesthesia in patients receiving perioperative bladder catheterization. Overactive bladder (OAB) and CRBD show similar symptoms; thus, drugs used for the management of OAB influence symptoms of CRBD. Trospium chloride has been found effective in managing resistant cases of OAB. We evaluated the efficacy of oral trospium on CRBD in the postoperative period. METHODS: Sixty-four male and female adult patients, with planned spinal surgery and requiring urinary bladder catheterization, were randomly divided into two groups of 32 each. Group T patients received 60 mg extended-release oral trospium (extended-release) 1 h before induction of anesthesia and Group C patients received a similar-looking placebo. The anesthetic technique was identical in both groups. The CRBD score was evaluated in the postoperative ward using a 4-point scale (1 = no discomfort, 2 = mild, 3 = moderate, 4 = severe). Readings were recorded on arrival (0 h), and 1 h, 2 h, and 6 h postoperatively. All patients received fentanyl for postoperative pain relief. RESULTS: The incidence of CRBD was significantly higher in group C than in group T at 0 h (66% vs 22%, P=0.001) and 1 h postoperatively (72% vs 28%, P=0.001). The incidence of moderate to severe CRBD was higher in group C at postoperative 2 h (82% vs 14%, P=0.004). There was no significant difference in postoperative fentanyl requirements. CONCLUSIONS: Pretreatment with 60 mg ER trospium reduced the incidence and severity of CRBD in the early postoperative period.

Urinary Urgency: A Symptom In Need Of A Cure.

Urgency, defined as "a sudden, compelling desire to pass urine which is difficult to defer", is not always reported by patients with overactive bladder, and is not usually described in these words. Urgency is known to have a strong negative impact on patients' quality of life and requires attention from healthcare professionals, as they play a key role in establishing the diagnosis and in deciding, together with the patient, the most appropriate treatment. This topic was debated during the symposium "Urinary Urgency: A Symptom in Need of a Cure?", held at the 11th Annual Meeting of the European Urogynaecology Association (EUGA) in October 2018 in Milan, Italy. The presentation of two clinical cases, those of a young, active woman and a retired teacher, illustrated the importance of this cornerstone symptom and demonstrated how fesoterodine may represent an important option in the management of this condition. The experts concluded that the physician should not leave urgency undeclared or untreated; that the patient should be involved in the choice of treatment; and that fesoterodine, which offers flexible dosing and has proven, consistent positive results on urgency episodes and urgency urinary incontinence, with very low/no risk of impairment of cognitive function, appears to be one of the good choices in the treatment of this symptom.

Qualitative Analysis of Factors Influencing Patient Persistence and Adherence to Prescribed Overactive Bladder Medication in UK Primary Care.

INTRODUCTION: Pharmacotherapy for overactive bladder (OAB) is generally associated with low rates of persistence and adherence. This study was conducted to explore the patient journey in a UK primary care setting (experiences, perceptions, attitudes, and levels of engagement and expectations) and identify self-reported reasons for patient non-adherence and/or non-persistence to medications for OAB. METHODS: This was a qualitative, non-interventional study involving one-to-one semi-structured, face-to-face or phone interviews with individuals aged 40-80 years, diagnosed with OAB, and currently taking, or having taken, either antimuscarinic or ß3-adrenoceptor agonist medications within the last 12 months. Thematic analyses of interview transcripts identified themes surrounding the participants' experiences with OAB. RESULTS: A total of 20 interviews were conducted (face-to-face, n = 13; telephone, n = 7). Interviews from five men and 13 women (mean age 70 years) were included in the final analysis. The most common OAB symptoms reported included urgency, frequency, incontinence and nocturia. Several key themes of factors influencing persistence and/or adherence to prescribed OAB medication were identified: patients' attitude and condition adaptation behaviour; support with treatment; unmet efficacy/tolerability expectations; drug/condition hierarchy. Non-adherence and/or non-persistence to OAB medication was largely intentional, with patients balancing side effects against perceived clinical benefits. Perceived lack of efficacy was the primary reason for discontinuing treatment. Other factors cited included side effects of medication (either experienced or a fear of future effects), a general aversion to long-term medication taking, drug/condition hierarchy relative to other comorbidities, and limited healthcare professional (HCP) support/engagement. Patients expressed condition adaptation behaviours to help self-manage their condition. CONCLUSION: Persistence and adherence to OAB medication may be suboptimal. HCPs might be able to improve persistence and adherence by fostering realistic treatment expectations and scheduling regular medication reviews. These measures may help optimise patient care and support more adherent behaviours, thus minimising the impact of undertreated OAB on patient quality of life. FUNDING: Innovate UK and Astellas Pharma Europe Ltd (APEL).

New Treatments for Asthma.

Asthma is a complex, heterogeneous chronic airway disease with high prevalence of uncontrolled disease. New therapies, including biologics, are now available to treat T2 high asthma. Treatment of T2 low asthma remains a challenge. Asthma guidelines need be to updated to incorporate new therapeutics.

Understanding Central Nervous System Effects of Deliriant Hallucinogenic Drugs through Experimental Animal Models.

Hallucinogenic drugs potently alter human behavior and have a millennia-long history of use for medicinal and religious purposes. Interest is rapidly growing in their potential as CNS modulators and therapeutic agents for brain conditions. Antimuscarinic cholinergic drugs, such as atropine and scopolamine, induce characteristic hyperactivity and dream-like hallucinations and form a separate group of hallucinogens known as "deliriants". Although atropine and scopolamine are relatively well-studied drugs in cholinergic physiology, deliriants represent the least-studied class of hallucinogens in terms of their behavioral and neurological phenotypes. As such, novel approaches and new model organisms are needed to investigate the CNS effects of these compounds. Here, we comprehensively evaluate the preclinical effects of deliriant hallucinogens in various animal models, their mechanisms of action, and potential interplay with other signaling pathways. We also parallel experimental and clinical findings on deliriant agents and outline future directions of translational research in this field.

Mirabegron is alternative to antimuscarinic agents for overactive bladder without higher risk in hypertension: a systematic review and meta-analysis.

PURPOSE: Mirabegron, a ß3-adrenoceptor agonist, was approved for overactive bladder (OAB), but worsened hypertension was a potential risk based on its mechanism of action. Besides, head to head comparisons were limited between mirabegron and antimuscarinic agents, the prior first-line pharmacotherapy of OAB. In this regard, we performed a systematic review and meta-analysis to compare their efficacy as well as safety, especially in blood pressure changes. MATERIALS AND METHODS: Literature search was conducted in PubMed, Medline and seven randomized clinical trial (RCT) register databases of WHO, EU, USA, Taiwan, China, Japan and Cochrane. Completed RCTs for OAB with mirabegron and antimuscarinics were identified and the last comprehensive search was run in August 2017. Cochrane risk of bias tool was used to assess the potential bias, and RevMan5 software was performed for meta-analysis. RESULTS: Seven eligible RCTs (four for mirabegron vs. tolterodine and three for mirabegron vs. solifenacin) were included and demonstrated similar efficacy in micturitions, incontinence, and nocturia between mirabegron and antimuscarinics. In hypertension issue, no statistical differences were showed in risk ratio (RR) of hypertension events, change of blood pressure from baseline and change of blood pressure from placebo for all participants. On the other hand, RR of dry mouth was significantly lower in mirabegron users. CONCLUSIONS: Mirabegron was not inferior effective in improving OAB symptoms compared with antimuscarinic agents. In addition, mirabegron presented lower incidence of dry mouth and not higher risk for hypertension. Therefore, mirabegron has potential to be an alternative therapeutic option for OAB control.

Assessment of inhibitory effects on major human cytochrome P450 enzymes by spasmolytics used in the treatment of overactive bladder syndrome.

BACKGROUND: The objective of this study was to examine the inhibitory potential of darifenacin, fesoterodine, oxybutynin, propiverine, solifenacin, tolterodine and trospium chloride on the seven major human cytochrome P450 enzymes (CYP) by using a standardized and validated seven-in-one cytochrome P450 cocktail inhibition assay. METHODS: An in vitro cocktail of seven highly selective probe substrates was incubated with human liver microsomes and varying concentrations of the seven test compounds. The major metabolites of the probe substrates were simultaneously analysed using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Enzyme kinetics were estimated by determining IC50 and Ki values via nonlinear regression. Obtained Ki values were used for predictions of potential clinical impact of the inhibition using a static mechanistic prediction model. RESULTS: In this study, 49 IC50 experiments were conducted. In six cases, IC50 values lower than the calculated threshold for drug-drug interactions (DDIs) in the gut wall were observed. In these cases, no increase in inhibition was determined after a 30 min preincubation. Considering a typical dosing regimen and applying the obtained Ki values of 0.72 µM (darifenacin, 15 mg daily) and 7.2 µM [propiverine, 30 mg daily, immediate release (IR)] for the inhibition of CYP2D6 yielded a predicted 1.9-fold and 1.4-fold increase in the area under the curve (AUC) of debrisoquine (CYP2D6 substrate), respectively. Due to the inhibition of the particular intestinal CYP3A4, the obtained Ki values of 14 µM of propiverine (30 mg daily, IR) resulted in a predicted doubling of the AUC for midazolam (CYP3A4 substrate). CONCLUSIONS: In vitro/in vivo extrapolation based on pharmacokinetic data and the conducted screening experiments yielded similar effects of darifenacin on CYP2D6 and propiverine on CYP3A4 as obtained in separately conducted in vivo DDI studies. As a novel finding, propiverine was identified to potentially inhibit CYP2D6 at clinically occurring concentrations.

Clinical and economic impact of mirabegron compared with antimuscarinics for the treatment of overactive bladder in Canada.

BACKGROUND: The ß3-adrenoceptor agonist, mirabegron, and antimuscarinic agents provide similar efficacy for the treatment of overactive bladder (OAB), but mirabegron appears to be associated with better persistence, perhaps due to an absence of anticholinergic side-effects. This study estimated the expected costs associated with the management of OAB in Canada from a societal perspective by utilizing real-world evidence. METHODS: An economic model with monthly cycles and a 1-year time horizon was developed to depict a treatment pathway for a hypothetical cohort of 100 patients with OAB. At model entry, patients receive mirabegron or an antimuscarinic. Patients who do not persist may switch treatment, undergo a minimally invasive procedure, or remain symptomatic (uncontrolled). The model includes direct costs (e.g. physician visits) and indirect costs (e.g. lost productivity). A one-way univariate sensitivity analysis assessed a ±20% variation in each of the key model inputs. RESULTS: At 1 year, a greater proportion of patients persisted on treatment with mirabegron compared with antimuscarinics (33% vs 15-23%), and a smaller proportion switched treatment (17% vs 20-22%). The number of healthcare visits (292 vs 299-304), pads used (74,098 vs 77,878-81,669), and work hours lost (4,497 vs 5,372-6,249) were all lower for mirabegron vs antimuscarinics. The estimated total annual cost of treatment per patient with mirabegron was $2,127.46 Canadian dollars (CAD) ($5.82 CAD/day) compared with $2,150.20-$2,496.69 CAD ($5.89-$6.84 CAD/day) for antimuscarinics. The one-way sensitivity analysis indicated the results are robust. CONCLUSIONS: Improved persistence observed in routine clinical practice with mirabegron appears to translate into benefits of reduced healthcare resource use, and lower direct and indirect costs of treatment compared with antimuscarinics. Overall, these data suggest that mirabegron may offer clinical and economic benefits for the management of patients with OAB in Canada.

Quantification of anticholinergic and sedative drug load with the Drug Burden Index: a review of outcomes and methodological quality of studies.

PURPOSE: The Drug Burden Index (DBI) is a non-invasive method to quantify patients' anticholinergic and sedative drug burden from their prescriptions. This systematic review aimed to summarise the evidence on the associations between the DBI and clinical outcomes and methodological quality of studies. METHODS: A search in PubMed and Embase (search terms: 'drug', 'burden', and 'index') was performed and experts were contacted. We excluded publications that did not report empirical results or clinical outcomes. Methodological quality was assessed using the Newcastle-Ottawa Scale. Potential omissions of relevant clinical outcomes and populations were studied. RESULTS: Of the 2998 identified publications, 21 were eligible. Overall, methodological quality of studies was good. In all but one study, adjustment was made for prevalent co-morbidity. The DBI was examined in diverse older individuals, i.e. both males and females from different settings and countries. However, no studies were conducted in other relevant patient groups, e.g. psychiatric patients. Exposure to anticholinergic and sedative drugs was thoroughly ascertained, though the specific calculation of the DBI differed across studies. Outcomes were assessed from medical records, record linkage or validated objective tests or questionnaires. Many studies found associations between the DBI and outcomes including hospitalisation, physical and cognitive function. Cognitive function and quality of life were understudied and the number and scope of longitudinal studies was limited. CONCLUSIONS: An accumulating body of evidence supports the validity of the DBI. Longitudinal studies of cognitive function and quality of life and in other patient groups, e.g. psychiatric patients, are warranted.

Fixed-Dose Combination Inhalers.

In asthma and chronic obstructive pulmonary disease (COPD), an important step in simplifying management and improving adherence with prescribed therapy is to reduce the dose frequency to the minimum necessary to maintain disease control. Fixed-dose combination (FDC) therapy might enhance compliance by decreasing the number of medications and/or the number of daily doses. Furthermore, they have the potential for enhancing, sensitizing, and prolonging the effects of monocomponents. Combination therapy with an inhaled corticosteroid (ICS) and a long-acting ß-agonist (LABA) is considered an important approach for treating patients with asthma and patients with severe COPD who have frequent exacerbations. Several ICS/LABA FDCs are now commercially available or will become available within the next few years for the treatment of COPD and/or asthma. Several studies demonstrate that there are a number of added benefits in using combinations of ß2-agonists and antimuscarinic agents. In particular, LABA/long-acting antimuscarinic agent (LAMA) combination seems to play an important role in optimizing bronchodilation. Several once-daily and twice-daily LABA/LAMA FDCs have been developed or are in clinical development. LAMA/ICS FDCs seem to be useful in COPD and mainly in asthma, in patients with severe asthma and persistent airflow limitation. The rationale behind the ICS/LABA/LAMA FDCs seems logical because all three agents work via different mechanisms on different targets, potentially allowing for lower doses of the individual agents to be used, accompanied by improved side effect profiles. In effect, in clinical practice, concomitant use of all three compounds is common, especially in more severe COPD but also in the treatment of adults with poorly controlled asthma despite maintenance treatment with high-dose ICS and a LABA.

Muscarinic Receptor Antagonists.

Parasympathetic activity is increased in patients with chronic obstructive pulmonary disease (COPD) and asthma and appears to be the major reversible component of airway obstruction. Therefore, treatment with muscarinic receptor antagonists is an effective bronchodilator therapy in COPD and also in asthmatic patients. In recent years, the accumulating evidence that the cholinergic system controls not only contraction by airway smooth muscle but also the functions of inflammatory cells and airway epithelial cells has suggested that muscarinic receptor antagonists could exert other effects that may be of clinical relevance when we must treat a patient suffering from COPD or asthma. There are currently six muscarinic receptor antagonists licenced for use in the treatment of COPD, the short-acting muscarinic receptor antagonists (SAMAs) ipratropium bromide and oxitropium bromide and the long-acting muscarinic receptor antagonists (LAMAs) aclidinium bromide, tiotropium bromide, glycopyrronium bromide and umeclidinium bromide. Concerns have been raised about possible associations of muscarinic receptor antagonists with cardiovascular safety, but the most advanced compounds seem to have an improved safety profile. Further beneficial effects of SAMAs and LAMAs are seen when added to existing treatments, including LABAs, inhaled corticosteroids and phosphodiesterase 4 inhibitors. The importance of tiotropium bromide in the maintenance treatment of COPD, and likely in asthma, has spurred further research to identify new LAMAs. There are a number of molecules that are being identified, but only few have reached the clinical development.