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.

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).

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.

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 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.

Saline versus Plasma-Lyte A in initial resuscitation of trauma patients: a randomized trial.

OBJECTIVE: We sought to compare resuscitation with 0.9% NaCl versus Plasma-Lyte A, a calcium-free balanced crystalloid solution, hypothesizing that Plasma-Lyte A would better correct the base deficit 24 hours after injury. BACKGROUND: Sodium chloride (0.9%) (0.9% NaCl), though often used for resuscitation of trauma patients, may exacerbate the metabolic acidosis that occurs with injury, and this acidosis may have detrimental clinical effects. METHODS: We conducted a randomized, double-blind, parallel-group trial (NCT01270854) of adult trauma patients requiring blood transfusion, intubation, or operation within 60 minutes of arrival at the University of California Davis Medical Center. Based on a computer-generated, blocked sequence, subjects received either 0.9% NaCl or Plasma-Lyte A for resuscitation during the first 24 hours after injury. The primary outcome was mean change in base excess from 0 to 24 hours. Secondary outcomes included 24-hour arterial pH, serum electrolytes, fluid balance, resource utilization, and in-hospital mortality. RESULTS: Of 46 evaluable subjects (among 65 randomized), 43% had penetrating injuries, injury severity score was 23 ± 16, 20% had admission systolic blood pressure less than 90 mm Hg, and 78% required an operation within 60 minutes of arrival. The baseline pH was 7.27 ± 0.11 and base excess -5.9 ± 5.0 mmol/L. The mean improvement in base excess from 0 to 24 hours was significantly greater with Plasma-Lyte A than with 0.9% NaCl {7.5 ± 4.7 vs 4.4 ± 3.9 mmol/L; difference: 3.1 [95% confidence interval (CI): 0.5-5.6]}. At 24 hours, arterial pH was greater [7.41 ± 0.06 vs 7.37 ± 0.07; difference: 0.05 (95% CI: 0.01-0.09)] and serum chloride was lower [104 ± 4 vs 111 ± 8 mEq/L; difference: -7 (95% CI: -10 to -3)] with Plasma-Lyte A than with 0.9% NaCl. Volumes of study fluid administered, 24-hour urine output, measures of resource utilization, and mortality did not significantly differ between the 2 arms. CONCLUSIONS: Compared with 0.9% NaCl, resuscitation of trauma patients with Plasma-Lyte A resulted in improved acid-base status and less hyperchloremia at 24 hours postinjury. Further studies are warranted to evaluate whether resuscitation with Plasma-Lyte A improves clinical outcomes.

Evaluation of distracting pain and clinical judgment in cervical spine clearance of trauma patients.

BACKGROUND: The concept of distracting pain (DP) is a controversial subjective confounder that often impedes the efficient and timely clearance of the cervical spine (C-spine). This study attempted to define DP more objectively and assess its true potential to mask the presence of C-spine injury. It also evaluated reliability and safety of clinical judgment in discounting the significance of pain peripheral to the neck (PP). METHODS: This prospective study included patients with a Glasgow Coma Score ≥14 at a level I trauma center presenting in a C-spine collar. Demographics, mechanism of injury, severity and location of all pain, and C-spine imaging data were obtained. Patient and examiner perception of DP were ascertained using the Verbal Numerical Rating Scale (VNRS) along with the examiner's clinical opinion as to the presence of a fracture. RESULTS: A total of 160 patients were studied: 65 % male, mean age 39 years, and 44 % presenting after a motor vehicle crash. In all, 16 % complained of neck pain (NP) and 82 % of PP. There were 134 patients without NP, 110 of whom (82 %) had PP. The mean VNRS in patients with no NP was 4.2; in patients with NP it was 4.8. When examined, 14 patients without NP exhibited posterior cervical tenderness, one of whom had a fracture (7 %). Of the patients with PP, 10 % stated it was DP. The mean VNRS described as DP by all patients was 7.5 but by clinician 6.5. VNRS described as not DP was 4.8 for both patients and clinicians. Overall, 8 of the 160 patients (5 %) had confirmed C-spine injuries. Regardless of NP or PP and its potentially distracting nature, clinicians believed no fracture was present in 95 % of all cases. Clinical impression was 98 % accurate. For patients with NP, clinical impression had a 91 % negative predictive value (NPV) and a 100 % a positive predictive value (PPV). In those without NP, the NPV was 99 % and the PPV 25 %. CONCLUSIONS: The concept of DP is subjective and unreliable as a method to mitigate missed C-spine injuries. If it is to be considered for use, DP should be defined as VNRS ≥5. Reliance on clinical impressions regardless of the presence or absence of NP or PP, distracting or otherwise, is accurate and safe.

Major complications, mortality, and resource utilization after open abdominal surgery: 0.9% saline compared to Plasma-Lyte.

OBJECTIVE: To assess the association of 0.9% saline use versus a calcium-free physiologically balanced crystalloid solution with major morbidity and clinical resource use after abdominal surgery. BACKGROUND: 0.9% saline, which results in a hyperchloremic acidosis after infusion, is frequently used to replace volume losses after major surgery. METHODS: An observational study using the Premier Perspective Comparative Database was performed to evaluate adult patients undergoing major open abdominal surgery who received either 0.9% saline (30,994 patients) or a balanced crystalloid solution (926 patients) on the day of surgery. The primary outcome was major morbidity and secondary outcomes included minor complications and acidosis-related interventions. Outcomes were evaluated using multivariable logistic regression and propensity scoring models. RESULTS: For the entire cohort, the in-hospital mortality was 5.6% in the saline group and 2.9% in the balanced group (P < 0.001). One or more major complications occurred in 33.7% of the saline group and 23% of the balanced group (P < 0.001). In the 3:1 propensity-matched sample, treatment with balanced fluid was associated with fewer complications (odds ratio 0.79; 95% confidence interval 0.66-0.97). Postoperative infection (P = 0.006), renal failure requiring dialysis (P < 0.001), blood transfusion (P < 0.001), electrolyte disturbance (P = 0.046), acidosis investigation (P < 0.001), and intervention (P = 0.02) were all more frequent in patients receiving 0.9% saline. CONCLUSIONS: Among hospitals in the Premier Perspective Database, the use of a calcium-free balanced crystalloid for replacement of fluid losses on the day of major surgery was associated with less postoperative morbidity than 0.9% saline.

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.

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.

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.

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.

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.

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.

A clustering of injury behaviors.

BACKGROUND: Alcohol is a well-known risk factor for injury. A number of other behaviors are also associated with injury risk. We hypothesized that risky drinking would be associated with other high risk behaviors, thereby delineating a need for behavioral interventions in addition to alcohol. METHODS: A consecutive sample of trauma patients was interviewed for drinking and risky behaviors including seat belt use, helmet use, and driving behaviors. The Alcohol Use Disorders Identification Test was used to screen for risky drinking and risky behavior questions were taken from validated questionnaires. Behaviors were ranked on a Likert scale ranging from a low to a high likelihood of the behavior or assessed the frequency of behavior in the past 30 days. An Alcohol Use Disorders Identification Test score of 8 or more was considered risky drinking for adults age 21 to 64, and 4 or more for ages 16 to 20 and over 65. Risky and nonrisky drinkers were compared on behavior risk items. A p value of less than 0.05 was considered significant. RESULTS: One hundred sixty patients (mean age, 36.8 years, 72% men,) were interviewed. Risky drinkers were more likely to drive after consuming alcohol, ride with drinking drivers, tailgate, weave in and out of traffic, and make angry gestures at other drivers (all p < 0.05). Risky drinkers were less likely to wear motorcycle helmets. However, risky drinkers were no more or less likely to talk on the cell phone while driving, to use seatbelts, or use turn signals. Although number of lifetime vehicle crashes were similar, risky drinkers were more likely to have been the party at fault for the crash (mean 1.09 vs. 0.64, p = 0.03). CONCLUSIONS: Factors other than alcohol increase injury risk in problem drinkers. Injury prevention programs performing alcohol interventions should consider including behavioral interventions along with alcohol reduction strategies. New screening and intervention programs should be developed for injury behaviors that increase risk but are not alcohol related.

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.