Fall/Fracture-Related Healthcare Costs and Their Association with Cumulative Anticholinergic Burden in People with Overactive Bladder.

BACKGROUND: Falls/fractures are major causes of morbidity and mortality among older adults and the resulting health consequences generate a substantial economic burden. Risk factors are numerous and include overactive bladder (OAB) and anticholinergic use. OBJECTIVES: We aimed to estimate the impact of falls/fractures on all-cause healthcare resource utilization and costs, according to levels of cumulative anticholinergic burden, among individuals with OAB. METHODS: Among a US cohort of adults with OAB (identified based on medical claims for OAB or OAB-specific medications), the frequency of resource utilization (outpatients visits, medication use, and hospitalizations) was examined according to level of anticholinergic burden. Anticholinergic burden was assessed cumulatively using a published measure, and categorized as no, low, medium, or high. Resource utilization prior to and after a fall/fracture was compared. Generalized linear models were used to examine overall and incremental changes in healthcare resource utilization and costs by fall/fracture status, and annual costs were predicted according to age, sex, fall/fracture status, and level of anticholinergic burden. RESULTS: The mean age of the OAB cohort (n = 154,432) was 56 years, 68% were female, and baseline mean anticholinergic burden was 266.7 (i.e. a medium level of burden); a fall/fracture was experienced by 9.9% of the cohort. All estimates of resource utilization were higher among those with higher levels of anticholinergic burden, regardless of fall/fracture status, and higher for all levels of anticholinergic burden after a fall/fracture. Among those with a fall/fracture, the highest predicted annual costs were observed among those aged 66-75 years with high anticholinergic burden (US$22,408 for males, US$22,752 for females). CONCLUSIONS: Falls/fractures were associated with higher costs, which increased with increasing anticholinergic burden.

Comparative Safety and Efficacy of Treatments for Overactive Bladder Among Older Adults: A Network Meta-analysis.

BACKGROUND: Cumulative exposure to one or more anticholinergic medications ("anticholinergic burden") is associated with an increased risk of adverse outcomes, particularly among older individuals. Mirabegron, an oral selective ß3-adrenergic receptor agonist, has demonstrated efficacy in managing the symptoms of overactive bladder without contributing to anticholinergic burden. However, it is not known whether the favorable safety profile of mirabegron relative to antimuscarinics varies with increasing age among a patient population who may have a high anticholinergic burden. OBJECTIVE: The primary objective of this study was to indirectly compare the safety and efficacy profile of mirabegron relative to antimuscarinics in older adults with overactive bladder. METHODS: A systematic literature review was conducted to identify randomized controlled trials that reported safety and efficacy endpoints among patients aged ≥ 65 years. Identified randomized controlled trials were subsequently synthesized via a network meta-analysis. Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines in designing, performing, and reporting the literature review were followed. In line with current best practices, the network meta-analysis was conducted using a Bayesian approach and according to the overall general guidance for evidence synthesis developed by the National Institute for Health and Care Excellence decision support unit. Estimates of relative safety were assessed via the odds ratio and estimates of relative efficacy were assessed via means and credible intervals. RESULTS: A total of 3078 abstracts, 300 of which underwent full-text screening, were identified using the search criteria. Twenty articles reporting on 21 randomized controlled trials were eligible for data extraction and synthesis. Following review, five safety and five efficacy endpoints were considered for inclusion in the network meta-analysis. Regarding findings typical of anticholinergic exposure in older adults, mirabegron was not associated with an increased odds of dry mouth (odds ratio 95% credible interval 0.76 [0.26-2.37]) or constipation (1.08 [0.39-3.02]) relative to placebo, whereas antimuscarinics were strongly associated with these events (odds ratio range 3.78-7.85 and 2.12-4.66, respectively). In this older population, mirabegron was associated with a similar odds of experiencing adverse event-related treatment discontinuations relative to placebo (0.99 [0.57-1.70]), while the odds of experiencing an adverse event-related treatment discontinuation for antimuscarinics had a range of 1.14-3.03 (in most cases, the association was mild). No increased odds of experiencing overall treatment-emergent adverse events was observed for mirabegron or antimuscarinics (odds ratio range 1.25-1.55), apart from fesoterodine (2.23 [1.37-3.37]). Finally, a similar treatment effect was observed across all efficacy endpoints between mirabegron and antimuscarinics in this older population. CONCLUSIONS: This study indicates that the safety and efficacy profile of mirabegron remains favorable compared with antimuscarinics among older adults. This includes safety outcomes typically associated with anticholinergic burden, which were less frequently observed in patients treated with mirabegron.

Antimuscarinic Discontinuation in Patients with Overactive Bladder in Nursing Homes: A Retrospective Study of Medicare Beneficiaries.

INTRODUCTION: Although antimuscarinics form the first-line therapy in overactive bladder (OAB), little is known regarding antimuscarinic discontinuation among OAB patients in nursing homes. This study examined treatment patterns and predictors of antimuscarinic discontinuation among long-term nursing home (LTNH) residents with OAB. METHODS: The study cohort included LTNH residents (defined as residents staying ≥ 101 consecutive days) from the Minimum Data Set linked 2013-2015 Medicare claims data. Patients with OAB were defined by OAB-related claims and medication codes. Treatment patterns and discontinuation (medication gap ≥ 30 days) were characterized by examining OAB-specific antimuscarinics prescribed during LTNH stays. The Andersen Behavioral Model was used to identify predisposing, enabling and need factors that predict discontinuation. Kaplan-Meier curves and multivariable Cox proportional hazards regression model were used to assess the unadjusted and adjusted times to discontinuation, respectively, among different antimuscarinics. RESULTS: The mean age of the study cohort (n = 11,012) was 81.6 years (± 8.5), 74.6% were female, and 89.8% were non-Hispanic White. The mean duration of nursing home stay was 530.1 (± 268.4) days. The most commonly prescribed OAB-specific antimuscarinic was oxybutynin (69.8%). Overall, 66.5% of the study cohort discontinued the index antimuscarinic. Multivariable Cox PH regression analysis revealed that compared to LTNH residents who initiated treatment with oxybutynin, treatment discontinuation was lower with solifenacin or fesoterodin and discontinuation was more frequent when treatment was initiated with tolterodine, darifenacin or trospium compared with oxybutynin. In addition, several need factors (comorbidities, medication use and anticholinergic burden, etc.) were associated with antimuscarinic discontinuation. CONCLUSION: About  two-thirds of LTNH residents with OAB discontinued their index antimuscarinic during their nursing home stay. There was significant variation in discontinuation based on the index antimuscarinic agent with lowest risk of discontiuation with solifenacin and fesoterodin. Concerted efforts to optimize antimuscarinic use are needed to improve the management of OAB in nursing homes.

Safety and Tolerability Results from the PILLAR Study: A Phase IV, Double-Blind, Randomized, Placebo-Controlled Study of Mirabegron in Patients ≥ 65 years with Overactive Bladder-Wet.

BACKGROUND: In older patients with overactive bladder (OAB), mirabegron, a ß3-adrenoreceptor agonist, represents an alternative treatment that may have a favorable risk-benefit profile. OBJECTIVES: Our objective was to further examine the safety and tolerability of mirabegron versus placebo treatment in patients aged ≥ 65 years with OAB-wet. METHODS: We conducted a 12-week, double-blind, randomized, placebo-controlled phase IV study to compare mirabegron with placebo. Community-dwelling patients aged ≥ 65 years with OAB-wet (one or more incontinence episode and three or more urgency episodes, and an average of eight or more micturitions/24 h over a 3-day diary) were randomized to receive placebo or mirabegron 25 mg/day (optional dose escalation to 50 mg/day at week 4 or 8). Safety analyses were performed for adverse events (AEs) and vital signs on all randomized patients who received one or more dose of study drug. RESULTS: Treatment-emergent AEs (TEAEs), the majority mild or moderate in severity, were reported in 39.4% of placebo patients and 44.2 and 49.8% of those who received mirabegron 25 mg or 50 mg, respectively. The most common TEAEs in mirabegron-treated patients were urinary tract infection, headache, and diarrhea. The incidence of TEAEs was slightly higher in mirabegron patients aged ≥ 75 years than in those aged < 75 years. There were no clinically meaningful differences in changes in vital signs from baseline to end of treatment for any treatment group, and no differences were observed between mirabegron and placebo treatment groups. TEAEs tended to occur early post exposure and were not dose related. CONCLUSIONS: Mirabegron treatment was well-tolerated in older adults with OAB-wet. Safety and tolerability were consistent with the known mirabegron safety profile. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov: NCT02216214.

Effect of mirabegron on cognitive function in elderly patients with overactive bladder: MoCA results from a phase 4 randomized, placebo-controlled study (PILLAR).

BACKGROUND: Antimuscarinics are often used for treatment of overactive bladder (OAB), but exposure to medications such as antimuscarinics that have anticholinergic properties has been linked to adverse cognitive effects. A phase 4 placebo-controlled study (PILLAR; NCT02216214) described the efficacy and safety of mirabegron, a ß3-adrenoreceptor agonist, for treatment of wet OAB in patients aged ≥65 years. This pre-planned analysis aimed to measure differences in cognitive function between mirabegron and placebo, using a rapid screening instrument for mild cognitive impairment: the Montreal Cognitive Assessment (MoCA). METHODS: Outpatients aged ≥65 years with wet OAB were randomized 1:1 to mirabegron or placebo, stratified by age (<75/≥75 years). There were no exclusion criteria regarding cognitive status. Patients randomized to mirabegron initially received 25 mg/day with an optional increase to 50 mg/day after week 4/8 based on patient/investigator discretion. The MoCA was administered at baseline and end of treatment (EoT, week 12). The study protocol was Independent Ethics Committee/Institutional Review Board-approved. RESULTS: Of the 887 randomized patients who received ≥1 dose of study drug, 72.3% were female, 79.5% were white, and 28.1% were aged ≥75 years. All patients had ≥1 comorbidity and 94.3% were receiving ≥1 concomitant medication. One third of patients had a history of psychiatric disorders, the most common being depression (17.2%), insomnia (15.7%), and anxiety (11.4%). Baseline mean (standard error, SE) MoCA total scores were 26.9 (0.1) and 26.8 (0.1) in the mirabegron and placebo groups, respectively. Among patients with MoCA data available at baseline/EoT, 27.1% (115/425) and 25.8% (106/411) of mirabegron and placebo group patients, respectively, had impaired cognitive function at baseline (MoCA total score <26). There was no statistically significant change in adjusted mean (SE) MoCA total score from baseline to EoT in the mirabegron group (-0.2 [0.1]) or the placebo group (-0.1 [0.1]). CONCLUSIONS: Treatment with mirabegron for 12 weeks did not contribute to drug-related cognitive side effects in patients aged ≥65 years, as measured by the MoCA. Furthermore, the pattern of change in cognition over time in an older OAB trial population does not appear to differ from that of subjects receiving placebo. TRIAL REGISTRATION: NCT02216214 (prospectively registered August 13, 2014).

Efficacy and Safety of Mirabegron versus Placebo Add-On Therapy in Men with Overactive Bladder Symptoms Receiving Tamsulosin for Underlying Benign Prostatic Hyperplasia: A Randomized, Phase 4 Study (PLUS).

PURPOSE: PLUS investigated the efficacy and safety of mirabegron add-on therapy in men with overactive bladder symptoms receiving tamsulosin for underlying lower urinary tract symptoms attributable to benign prostatic hyperplasia. MATERIALS AND METHODS: In this phase 4 study a 4-week 0.4 mg tamsulosin run-in period was followed by a 12-week, randomized, double-blind, treatment period in which patients initially received 25 mg mirabegron or placebo add-on therapy. At 4 weeks doses were titrated to 50 mg mirabegron or placebo equivalent. Efficacy end points were changes from baseline to end of treatment in mean number of micturitions per day (primary), mean volume voided per micturition, number of urgency episodes per day, total urgency and frequency score, and total International Prostate Symptom Score (secondary). Safety assessments included treatment emergent adverse events, and post-void residual volume, and maximum urinary flow measurements. RESULTS: Of the 676 men most were 65 years old or older (380, 56.2%). Tamsulosin plus mirabegron was statistically superior to tamsulosin plus placebo in reducing the mean number of micturitions per day (-2.00 vs -1.62; adjusted difference -0.39; 95% CI -0.76, -0.02). Statistically superior results were noted for tamsulosin plus mirabegron in mean volume voided per micturition, urgency episodes per day, and total urgency and frequency score (not International Prostate Symptom Score). Higher overall treatment emergent adverse event rates were observed with tamsulosin plus placebo, although higher rates of drug related treatment emergent adverse events were noted with tamsulosin plus mirabegron. Urinary retention rates were higher in the tamsulosin plus mirabegron group. Post-void residual volume and maximum urinary flow results were not clinically meaningful. CONCLUSIONS: The results of PLUS underscore the utility of mirabegron add-on therapy to treat men with overactive bladder symptoms receiving tamsulosin for benign prostatic hyperplasia.

Efficacy, safety, and tolerability of mirabegron in patients aged ≥65yr with overactive bladder wet: a phase IV, double-blind, randomised, placebo-controlled study (PILLAR).

BACKGROUND: The majority of patients with overactive bladder (OAB) are aged >65yr. There has been no prospectively designed study assessing treatment efficacy with the ß3-adrenoreceptor agonist, mirabegron, specifically in this age group. OBJECTIVE: A phase IV study comparing flexibly dosed mirabegron versus placebo in elderly patients with OAB and urgency incontinence. DESIGN, SETTING, AND PARTICIPANTS: Community-dwelling patients aged ≥65yr with OAB for ≥3mo. INTERVENTION: Following a 2-wk placebo run in, patients with one or more incontinence episodes, three or more urgency episodes, and an average of eight or more micturitions/24h were randomised 1:1 to double-blind 25mg/d mirabegron or matched placebo, for 12wk. After week 4 or 8, the dose could be increased to 50mg/d mirabegron/matched placebo based on patient and investigator discretion. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Coprimary endpoints: change from baseline to end of treatment (EOT) in the mean numbers of micturitions/24h and incontinence episodes/24h. Secondary endpoints: change from baseline to EOT in the mean volume voided/micturition, mean number of urgency episodes/24h, and mean number of urgency incontinence episodes/24h. Analysis of covariance (ANCOVA) was used for the mean number of micturitions/24h, mean volume voided/micturition, and mean number of urgency episodes/24h. Stratified rank ANCOVA was used for the mean numbers of incontinence episodes/24h and urgency incontinence episodes/24h. RESULTS AND LIMITATIONS: Statistically significant improvements were observed for mirabegron versus placebo in change from baseline to EOT in the mean number of micturitions/24h, mean number of incontinence episodes/24h, mean volume voided/micturition, mean number of urgency episodes/24h, and mean number of urgency incontinence episodes/24h. Safety and tolerability were consistent with the known mirabegron safety profile. CONCLUSIONS: Mirabegron efficacy, safety, and tolerability over 12 wk were confirmed in patients aged ≥65yr with OAB and incontinence. PATIENT SUMMARY: We examined the effect of mirabegron compared with placebo in people aged 65yr or older with overactive bladder and incontinence. Mirabegron improved the symptoms of overactive bladder compared with placebo. Side effects were similar to those already known for mirabegron.

Factors Associated with Improvements in Patient-Reported Outcomes During Mirabegron or Antimuscarinic Treatment of Overactive Bladder Syndrome: A Registry Study (PERSPECTIVE).

INTRODUCTION: Patient-reported outcomes (PROs) provide valuable insights about the effectiveness of overactive bladder (OAB) treatments. The aim of PERSPECTIVE (a Prospective, non-intErventional Registry Study of PatiEnts initiating a Course of drug Therapy for overactIVE bladder) was to provide real-world evidence from the USA and Canada on patient-perceived effectiveness and safety of mirabegron and antimuscarinics for treating OAB symptoms. METHODS: This prospective, non-interventional registry followed adult patients with OAB who were starting treatment with mirabegron or antimuscarinics. All treatment decisions were made at the discretion of the treating healthcare provider with no mandatory visits after enrollment. The primary objective was to identify factors associated with improved treatment effectiveness from a patient perspective mainly using the OAB Questionnaire Short-Form (OAB-q SF). The form was sent to patients via email link at baseline and months 1, 3, 6, and 12. Treatment-emergent adverse event (TEAE) data were collated from investigator reports. RESULTS: Overall, 1514 patients were included (female 73.5%, mean age 62.2 years). Mirabegron was initiated by 613 patients and antimuscarinics by 901 patients. A PRO response rate of approximately 60% was achieved (575 patients did not complete baseline PROs). Similar improvements in OAB-q SF symptom bother score and health-related quality of life (HRQoL) total score were observed for mirabegron and antimuscarinic initiators. Covariate-adjusted models demonstrated that worse baseline PRO score, Hispanic ethnicity, being treatment naïve, and use of complementary/supportive OAB therapies at baseline were significantly associated with greater improvements in both scores. The most frequent TEAEs were gastrointestinal disorders (dry mouth, constipation, and nausea) and nervous system disorders (headache, somnolence, and dizziness). CONCLUSION: There are no differences between mirabegron and antimuscarinics in terms of patient-reported OAB symptom bother and HRQoL. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02386072. FUNDING: Astellas Pharma Global Development, Inc. Plain language summary available for this article.

Cardiovascular safety of mirabegron: analysis of an integrated clinical trial database of patients with overactive bladder syndrome.

Mirabegron is a ß3-adrenoreceptor agonist used for the treatment of overactive bladder syndrome. We evaluated the cardiovascular (CV) safety of mirabegron using pooled data from 13 studies. The analysis included 13,396 patients who received ≥1 dose of mirabegron (25 mg/50 mg) or comparator antimuscarinics (solifenacin 2.5 mg/5 mg/10 mg or tolterodine extended release 4 mg) as monotherapies, or placebo. We focused on changes in blood pressure and CV adverse events. Baseline CV risk factors had an imbalanced effect on subsequent CV adverse events. The frequency of these adverse events was comparable for overactive bladder treatments (0.4%-1.5%) and placebo (0.9%). Changes from baseline in blood pressure were similar for the overactive bladder treatments and placebo, and did not confer increased risk of CV adverse events. Multivariate analyses demonstrated that baseline CV risk factors (history of arrhythmia, history of coronary artery disease, and history of stroke/transient ischemic attack) were significantly associated with subsequent CV adverse events in the trials, whereas overactive bladder therapies were not. In conclusion, using an analytical approach to carefully control for CV characteristics of patients in these trials demonstrated no evidence of increased CV risk for mirabegron or antimuscarinics over placebo in the treatment of overactive bladder syndrome.

A Prospective, non-intErventional Registry Study of PatiEnts initiating a Course of drug Therapy for overactIVE bladder (PERSPECTIVE): Rationale, design, and methodology.

INTRODUCTION: Pharmacotherapy of overactive bladder (OAB) typically involves treatment with an antimuscarinic or mirabegron, a ß3-adrenoceptor agonist, but real-world evidence on their use, including treatment access, persistence, and switching, is limited. Here, we describe the design of a prospective, multicenter, non-interventional registry of patients beginning a new course of OAB pharmacological therapy in routine clinical practice. METHODS: Adults with an OAB diagnosis for at least 3 months who either initiated a new course of mirabegron or antimuscarinic, or who switched therapy were enrolled into PERSPECTIVE (a Prospective, non-intErventional Registry Study of PatiEnts initiating a Course of drug Therapy for overactIVE bladder). The primary objective was to identify factors associated with improved OAB treatment effectiveness from a patient perspective. Secondary objectives were to compare persistence rates, reasons for discontinuation, and switching patterns between patients taking mirabegron or antimuscarinics. Healthcare centers and sites involving medical specialties who routinely participate in the care and treatment of patients with OAB (e.g., gynecology, urology, and primary care practices) were targeted for recruitment. Patient-reported outcomes (PROs), including quality of life, symptom bother, and treatment satisfaction from OAB-validated scales, were collected at baseline, months 1, 3, 6, and 12, and when patients switched or discontinued their current OAB medication. CONCLUSIONS: PERSPECTIVE is the first real-world observational study in the United States and Canada on clinical and patient perspectives in OAB management. Recruitment was reflective of centers where patients are treated for OAB to maximize generalizability to the real-world population. TRIAL REGISTRATION: ClinicalTrials.gov, ID number NCT02386072 (date of registration March 6, 2015).

Impact of Fluid Choice in Systemic Inflammatory Response Syndrome Patients on Hospital Cost Savings.

BACKGROUND: There is growing evidence of the benefits of intravenous fluid therapy with balanced crystalloids over 0.9% 'normal' saline. This analysis evaluated the economic impact of increasing usage of a calcium-free balanced crystalloid solution (BAL) in patients with systemic inflammatory response syndrome (SIRS) on an annual hospital budget. METHODS: An Excel®-based economic model was developed to estimate costs associated with increased BAL usage (i.e., use in a greater proportion of patients), from the US hospital perspective, over a 5-year time horizon. Clinical inputs were based on the results of a retrospective Electronic Health Record (EHR) database analysis identifying significantly fewer complications among SIRS patients receiving predominantly BAL versus saline. Complication-associated costs, adjusted to 2015, were obtained from published reports. Scenario analyses examined cost impacts for hospitals of various sizes, with different BAL adoption levels and rates. RESULTS: Base-case scenario analysis (300-bed hospital, 80% occupancy, current and year 5 BAL usage in 5 and 75% of SIRS patients, respectively, exponential year-over-year adoption) showed year 1 hospital savings of US$29,232 and cumulative 5-year savings of US$1.16M. Cumulative 5-year pharmacy savings were US$172,641. Scenario analyses demonstrated increasing cumulative 5-year savings with increasing hospital size, year 5 BAL usage in greater proportions of patients, and rapid/early BAL adoption. CONCLUSIONS: Increased BAL usage represents an opportunity for hospitals and pharmacy departments to reduce complication-related costs associated with managing SIRS patients. The model suggests that savings could be expected across a range of scenarios, likely benefiting hospitals of various sizes and with different adoption capabilities.

Patient-reported outcomes in patients with overactive bladder treated with mirabegron and tolterodine in a prospective, double-blind, randomized, two-period crossover, multicenter study (PREFER).

BACKGROUND: The PREFER study was an assessment of medication tolerability, treatment preference and symptom improvement during treatment with mirabegron (M) and tolterodine (T) extended release (ER) in patients with overactive bladder (OAB). In this analysis of PREFER, patient-reported outcomes (PROs) were assessed during treatment. METHODS: PREFER was a two-period, 8-week crossover, double-blind, phase IV study (NCT02138747) of treatment-naïve adults with OAB ≥3 months randomized to 1 of 4 treatment sequences (M/T; T/M; M/M; T/T), separated by a 2-week washout. Tolterodine ER was dosed at 4 mg for 8 weeks and mirabegron was dosed at 25 mg for 4 weeks then increased to 50 mg for the next 4 weeks. At each visit, PROs related to treatment satisfaction, quality of life and symptom bother were assessed using the OAB Satisfaction (OAB-S; 3 independent scales/5 single-item overall assessments), OAB-q (total health-related QoL [HRQoL] and subscales [Sleep, Social, Coping, Concern] and Symptom Bother scale) and Patient Perception of Bladder Condition (PPBC) questionnaires. Responder rates were reported for OAB-q subscales based on a minimal important difference (MID; ≥ 10-point improvement) and OAB-S Medication Tolerability score ≥ 90. RESULTS: In total, 358 randomized patients received ≥1 dose of double-blind study medication and completed ≥1 post-baseline value (OAB-S scale, OAB-q, PPBC): M/T (n = 154), T/M (n = 144), M/M (n = 30) or T/T (n = 30). At end of treatment (EoT), mirabegron and tolterodine ER were associated with similar mean improvements in 7 of the 8 OAB-S scores investigated, OAB-q scales and PPBC. A higher percentage of patients achieved clinically relevant improvements (MID) in OAB-q scales and OAB-S Medication Tolerability score during treatment with mirabegron than tolterodine ER. CONCLUSIONS: On average, patients with OAB experienced improvements in treatment satisfaction, HRQoL and symptom bother that were of a similar magnitude during treatment with mirabegron or tolterodine ER. However, during mirabegron treatment, patients were more likely to achieve clinically relevant improvements in tolerability and HRQoL (as measured by the MID for the OAB-q or an OAB-S Medication Tolerability score ≥ 90) than during tolterodine ER treatment. TRIAL REGISTRATION: NCT02138747 ; registered May 13, 2014.

A prospective, double-blind, randomized, two-period crossover, multicenter study to evaluate tolerability and patient preference between mirabegron and tolterodine in patients with overactive bladder (PREFER study).

INTRODUCTION AND HYPOTHESIS: The objective of this study was to assess the tolerability and treatment preference in patients with overactive bladder (OAB) treated with mirabegron or tolterodine. METHODS: This was a two-period, 8-week crossover, double-blind, phase IV study (PREFER; NCT02138747) in treatment-naive adults with OAB for 3 months or longer randomized to one of four treatment sequences in a 5:5:1:1 ratio (mirabegron/tolterodine, tolterodine/mirabegron, mirabegron/mirabegron, or tolterodine/tolterodine), separated by a washout period of 2 weeks. The primary endpoint was drug tolerability using the Medication Tolerability scale of the OAB Treatment Satisfaction (OAB-S) questionnaire at end of treatment (EoT). Period-by-treatment interactions were analyzed to determine any effect of drug order. Patient preference, change from baseline in OAB symptoms, and treatment-emergent adverse events (TEAEs) were assessed. RESULTS: A total of 358 randomized patients completed the OAB-S Medication Tolerability scale questionnaire at one or more visits after the baseline evaluation. The mean (95% CI) OAB-S Medication Tolerability scores were significantly higher (better tolerability) for mirabegron (86.29 [83.50, 89.08]) than for tolterodine (83.40 [80.59, 86.20]; p = 0.004). The period-by-treatment interaction was not significant (p = 0.955). Improvements in OAB-S Medication Tolerability scores at EoT were more evident in women, patients aged ≥65 years, and in patients without baseline incontinence, and were greater with mirabegron than with tolterodine extended release. There were no significant differences in patient preference or improvements in OAB symptoms. Significant differences in favor of mirabegron were observed for anticholinergic TEAEs (20.4% vs. 27.4%; p = 0.042) and specifically for gastrointestinal disorders (14.7% vs. 22.5%; p = 0.015). CONCLUSIONS: Tolerability of mirabegron was significantly higher than that of tolterodine, and patient preference and improvements in OAB symptoms were comparable. Both treatments were well tolerated; however, anticholinergic side effects were higher with tolterodine.

A prospective study of elderly initiating mirabegron versus antimuscarinics: Patient reported outcomes from the Overactive Bladder Satisfaction Scales and other instruments.

AIMS: To understand differences in patient reported outcomes (PRO) between patients initiating mirabegron or an antimuscarinic using a validated PRO instrument, OAB-Satisfaction (OAB-S). METHODS: This prospective observational study used real-time prescription claims from Humana to identify Medicare patients initiating mirabegron or an antimuscarinic to participate in a series of three phone surveys over ninety days. RESULTS: A total of 1897 mirabegron and 2444 randomly selected antimuscarinic initiators were identified; 174 mirabegron and 193 antimuscarinic initiators completed all three surveys. Among responders, mirabegron initiators were slightly older (76 vs 75 years, P = 0.032), included more males (32% vs 23%, P = 0.044), more likely to have prior OAB treatment (21% vs 13%, P = 0.048), and had greater medication burden (number of unique medications: 10.0 vs 8.7, P = 0.014). There were no between-group differences at any time or on any OAB-S scale. There were significant within-group differences at follow-up compared to baseline for OAB-S scales: "impact on daily living," with improvement over the 90-day survey period for both mirabegron (P = 0.008) and antimuscarinic (P < 0.001); "interruption of day-to-day life," with improvement for both mirabegron (P < 0.001) and antimuscarinic (P < 0.001); and improvement in "OAB control" for mirabegron (P < 0.001) and antimuscarinic (P < 0.001). CONCLUSIONS: Mirabegron initiators tended to be older, had a greater number of unique medications and previously tried prescriptions to treat OAB; nonetheless, mirabegron, and antimuscarinic initiators reported similar trends in improvement in PROs over the first 90 days of treatment. Significant improvement in daily impact of OAB was observed after treatment initiation; however, no significant differences between groups were observed.

Impact of Overactive Bladder Step Therapy Policies on Medication Utilization and Expenditures Among Treated Medicare Members.

BACKGROUND: The impact of formulary management strategies on utilization and expenditures in overactive bladder (OAB) treatment has not been extensively investigated. In 2013, step therapy (ST) policies for 2 branded OAB treatments, mirabegron and fesoterodine, were removed from Humana Medicare Advantage Prescription Drug (MAPD) plans and Medicare prescription drug plans (PDP), allowing for an examination of the effect of ST policies on OAB medication use patterns and costs. OBJECTIVE: To assess the impact of removal of formulary restriction policies for mirabegron and fesoterodine on medication utilization patterns and costs associated with OAB treatment in Medicare patients. METHODS: A retrospective cross-sectional study design was utilized. Subjects included individuals enrolled in Humana MAPD plans or PDPs, aged ≥ 65 years, with ≥ 1 prescription for an OAB medication in 2013. Patient demographic characteristics, OAB medication utilization, and pharmacy cost trends in 2013 were described. OAB medication use was calculated as the number of 30-day-supply equivalent medication claims and reported as a percentage of the total number of 30-day-supply equivalent claims across all OAB products. OAB medication expenditures were calculated as a percentage of the sum of pharmacy costs for OAB medications and reported separately for each month and drug during 2013. Temporal trends of OAB medication utilization and expenditures in 2013 were calculated using ordinary least squares regression. RESULTS: Of 194,511 patients, trends in utilization of OAB medications indicated that on average, there was a statistically significant monthly increase in utilization of mirabegron (regression coefficient [B] = 274; P < 0.001; 95% CI: 218, 330), fesoterodine (B = 167; P < 0.001; 95% CI = 129, 205), oxybutynin extended release (ER; B = 357; P = 0.011; 95% CI = 99, 614), and trospium ER (B = 33; P = 0.001; 95% CI = 17, 50) and statistically significant decreases in utilization of solifenacin (B = -202; P = 0.048; 95% CI = -402, -2), tolterodine ER (B = -287; P = 0.002; 95% CI = -437, -137), darifenacin (B = -94; P < 0.001; 95% CI = -128, -61), and trospium immediate release (IR; B = -22; P = 0.001; 95% CI = -32, -12). Total OAB medication expenditures significantly increased an average of 0.12% for each month during the course of 2013 (B = 0.12; P = 0.026; 95% CI = 0.017, -0.223). While monthly oxybutynin IR utilization did not change significantly throughout 2013 (B = 228; P = 0.169; 95% CI = -114, -570), it demonstrated the largest average monthly expenditure increase (B = 0.082; P < 0.001; 95% CI = 0.056, 0.108). When removing oxybutynin IR costs from the total OAB medication costs, the trend in total OAB medication average monthly expenditures was not significant (B = 0.038; P = 0.365; 95% CI = -0.051, -0.126). An over 4-fold per-unit-cost increase for oxybutynin IR was noted. CONCLUSIONS: Utilization of 2 branded OAB products increased in the months after ST removal with minimal cost impact. One of the possible reasons total OAB expenditures increased may have been due to the increased cost of the largest-volume generic product, oxybutynin IR. DISCLOSURES: This research was funded by Astellas Pharma Global Development and was conducted as part of the Astellas-Humana Research Collaboration. Ng, Kristy, Schermer, and Bradt are employees of Astellas. Astellas manufactures mirabegron (Myrbetriq) and solifenacin (VESIcare). Abbass, Caplan, Collins, and Suehs are employees of Comprehensive Health Insights, a subsidiary of Humana, which received funding from Astellas for this study. Suehs owns stock in Humana. Chan is an employee of Humana Pharmacy Solutions. Portions of this study were presented as a poster at Academy of Managed Care Pharmacy Nexus 2015; October 26-29, 2015; Orlando, Florida. Study concept and design were contributed by Ng, Chan, Suehs, and Abbass, along with Collins. Abbass took the lead in data collection, along with Collins and with assistance from Caplan, Chan, and Suehs. Data interpretation was provided by Kristy and Bradt, along with Abbass, Caplan, Ng, Suehs, Collins, and Chan. The manuscript was written primarily by Caplan, along with Schermer, Suehs, and Abbass, and revised by Caplan, Schermer, and Ng, along with the other authors.

A randomized trial of Plasma-Lyte A and 0.9 % sodium chloride in acute pediatric gastroenteritis.

BACKGROUND: Compare the efficacy and safety of Plasma-Lyte A (PLA) versus 0.9 % sodium chloride (NaCl) intravenous (IV) fluid replacement in children with moderate to severe dehydration secondary to acute gastroenteritis (AGE). METHODS: Prospective, randomized, double-blind study conducted at eight pediatric emergency departments (EDs) in the US and Canada (NCT#01234883). The primary outcome measure was serum bicarbonate level at 4 h. Secondary outcomes included safety and tolerability. The hypothesis was that PLA would be superior to 0.9 % NaCl in improvement of 4-h bicarbonate. Patients (n = 100) aged ≥6 months to <11 years with AGE-induced moderate-to-severe dehydration were enrolled. Patients with a baseline bicarbonate level ≤22 mEq/L formed the modified intent to treat (mITT) group. RESULTS: At baseline, the treatment groups were comparable except that the PLA group was older. At hour 4, the PLA group had greater increases in serum bicarbonate from baseline than did the 0.9 % NaCl group (mean ± SD at 4 h: 18 ± 3.74 vs 18.0 ± 3.67; change from baseline of 1.6 and 0.0, respectively; P = .004). Both treatment groups received similar fluid volumes. The PLA group had less abdominal pain and better dehydration scores at hour 2 (both P = .03) but not at hour 4 (P = 0.15 and 0.08, respectively). No patient experienced clinically relevant worsening of laboratory findings or physical examination, and hospital admission rates were similar. One patient in each treatment group developed hyponatremia. Four patients developed hyperkalemia (PLA:1, 0.9 % NaCl:3). CONCLUSION: In comparison with 0.9 % NaCl, PLA for rehydration in children with AGE was well tolerated and led to more rapid improvement in serum bicarbonate and dehydration score. TRIAL REGISTRATION: NCT#01234883 (Registration Date: November 3, 2010).

Impact of intravenous fluid composition on outcomes in patients with systemic inflammatory response syndrome.

INTRODUCTION: Intravenous (IV) fluids may be associated with complications not often attributed to fluid type. Fluids with high chloride concentrations such as 0.9 % saline have been associated with adverse outcomes in surgery and critical care. Understanding the association between fluid type and outcomes in general hospitalized patients may inform selection of fluid type in clinical practice. We sought to determine if the type of IV fluid administered to patients with systemic inflammatory response syndrome (SIRS) is associated with outcome. METHODS: This was a propensity-matched cohort study in hospitalized patients receiving at least 500 mL IV crystalloid within 48 hours of SIRS. Patient data was extracted from a large multi-hospital electronic health record database between January 1, 2009, and March 31, 2013. The primary outcome was in-hospital mortality. Secondary outcomes included length of stay, readmission, and complications measured by ICD-9 coding and clinical definitions. Outcomes were adjusted for illness severity using the Acute Physiology Score. Of the 91,069 patients meeting inclusion criteria, 89,363 (98%) received 0.9% saline whereas 1706 (2%) received a calcium-free balanced solution as the primary fluid. RESULTS: There were 3116 well-matched patients, 1558 in each cohort. In comparison with the calcium-free balanced cohort, the saline cohort experienced greater in-hospital mortality (3.27% vs. 1.03%, P <0.001), length of stay (4.87 vs. 4.38 days, P = 0.016), frequency of readmission at 60 (13.54 vs. 10.91, P = 0.025) and 90 days (16.56 vs. 12.58, P = 0.002) and frequency of cardiac, infectious, and coagulopathy complications (all P < 0.002). Outcomes were defined by administrative coding and clinically were internally consistent. Patients in the saline cohort received more chloride and had electrolyte abnormalities requiring replacement more frequently (P < 0.001). No differences were found in acute renal failure. CONCLUSIONS: In this large electronic health record, the predominant use of 0.9% saline in patients with SIRS was associated with significantly greater morbidity and mortality compared with predominant use of balanced fluids. The signal is consistent with that reported previously in perioperative and critical care patients. Given the large population of hospitalized patients receiving IV fluids, these differences may confer treatment implications and warrant corroboration via large clinical trials. TRIAL REGISTRATION: NCT02083198 clinicaltrials.gov; March 5, 2014.

Does saline resuscitation affect mechanisms of coagulopathy in critically ill trauma patients? An exploratory analysis.

Metabolic acidosis has been implicated in the development of coagulopathy, although the specific mechanisms have not been well characterized. We sought to explore whether resuscitation of injured patients with a balanced crystalloid solution affects coagulation, as measured by endogenous thrombin potential (ETP) and thromboelastography (TEG). We performed an exploratory analysis of a subset of subjects enrolled in a randomized trial comparing the effect of resuscitation with isotonic saline versus Plasma-Lyte A (PLA) on acidosis and electrolyte abnormalities. We collected plasma at admission and 6 h later for subsequent ETP and TEG analysis and compared subjects receiving isotonic saline to those receiving PLA. Among 18 evaluated subjects, baseline characteristics, including ETP and TEG parameters, were similar between the two arms. At 6 h, subjects receiving isotonic saline were more acidemic. At 6 h, there were no differences in ETP parameters between groups; however, TEG results showed the time from initial clot formation to an amplitude of 20 mm (K) was shorter (3.8 ±â€Š2.1 vs. 7.2 ±â€Š2.8 s) and the rapidity of fibrin build-up and cross-linking (α angle) was significantly greater (41 ±â€Š8 vs. 24 ±â€Š15 deg) for the PLA group than in the isotonic saline group. Relative to PLA, isotonic saline does not alter thrombin generation, but isotonic saline and PLA may differentially impact clotting factor availability. The shorter time to reach prespecified clot amplitude and the increased rate of fibrin generation imply faster amplification of clotting factors with PLA without effect on latency time or clot strength.