Comparative Efficacy of Neoadjuvant Nivolumab Plus Chemotherapy versus Conventional Comparator Treatments in Resectable Non-Small-Cell Lung Cancer: A Systematic Literature Review and Network Meta-Analysis.

BACKGROUND: This study aimed to estimate the relative efficacy of neoadjuvant nivolumab in combination with chemotherapy (neoNIVO + CT) compared to relevant treatments amongst resectable non-metastatic non-small-cell lung cancer (rNSCLC) patients. METHODS: Treatment comparisons were based on a network meta-analysis (NMA) using randomized clinical trial data identified via systematic literature review (SLR). The outcomes of interest were event-free survival (EFS) and pathological complete response (pCR). NeoNIVO + CT was compared to neoadjuvant chemotherapy (neoCT), neoadjuvant chemoradiotherapy (neoCRT), adjuvant chemotherapy (adjCT), and surgery alone (S). Due to the potential for effect modification by stage, all-stage and stage-specific networks were considered. Fixed-effect (FE) and random-effects Bayesian NMA models were run (EFS = hazard ratios [HR]; pCR = odds ratios [OR]; 95% credible intervals [CrI]). RESULTS: Sixty-one RCTs were identified (base case = 9 RCTs [n = 1978 patients]). In the all-stages FE model, neoNIVO + CT had statistically significant EFS improvements relative to neoCT (HR = 0.68 [95% CrI: 0.49, 0.94]), S (0.59 [0.42, 0.82]), adjCT (0.66 [0.45, 0.96]), but not relative to neoCRT (HR = 0.77 [0.52, 1.16]). NeoNIVO + CT (5 RCTs) had statistically significant higher odds of pCR relative to neoCT (OR = 12.53 [5.60, 33.82]) and neoCRT (7.15 [2.31, 24.34]). Stage-specific model findings were consistent. CONCLUSIONS: This NMA signals improved EFS and/or pCR of neoNIVO + CT relative to comparators among patients with rNSCLC.

Toenail Onychomycosis with or without Diabetes in Canada: Patient Treatment Preferences and Health State Utilities.

Background: Toenail onychomycosis affects approximately 6.7% of Canadians. Symptoms include nail discolouration/disfiguration and pain; psychosocial impacts contribute to reduced health-related quality-of-life. Comorbid diabetes increases the risk of complications and exacerbates burden. Treatment may include topical therapy and/or oral agents. Purpose: To understand toenail onychomycosis treatment preferences, and to quantify the impact of toenail onychomycosis, with or without diabetes, on patient well-being. Methods: Adults living in Canada with self-reported, physician-diagnosed, toenail onychomycosis were recruited online. A discrete choice experiment was used to quantify treatment preferences. Scenarios were randomized; data were analyzed using conditional logit regression. Health state utilities were estimated using the Health Utilities Index Mark 3®. Results were stratified by diabetes status and toenail onychomycosis severity; the Wilcoxon Rank Sum test was used to assess between-group utility differences. Results: Three-hundred thirteen participants with toenail onychomycosis were included (161 had comorbid diabetes; 61.3%, severe onychomycosis). The mean age was 57.7 years; 55.9% were male. Treatment attributes with statistically significant impacts on patient preferences were efficacy (odds ratio [OR],1.04; 95% confidence interval [CI], 1.02-1.05 per 1% increased treatment success), administration method (one pill versus topical nail lacquer reference, 1.14; 1.04-1.26; topical solution applicator versus reference: 1.15; 1.03-1.29), severe adverse events (0.85; 0.80-0.90 per 1% increased risk), and risk of potential pharmacodynamic (0.80; 0.76-0.85) and alcohol (0.93; 0.88-0.98) interactions; preferences were more pronounced for efficacy and avoiding severe adverse events among toenail onychomycosis patients with comorbid diabetes. The mean (95% CI) utility value was 0.73 (0.70-0.75) overall, and statistically significantly lower (p=0.02) for toenail onychomycosis patients with diabetes (0.70; CI, 0.66-0.73) than those without (0.76; CI, 0.72-0.79). Conclusion: Among patients with toenail onychomycosis, the presence of diabetes was associated with differing treatment-related preferences. Utility values for patients with toenail onychomycosis represent a significant decline from full health that is exacerbated by comorbid diabetes.

Long-term comparative efficacy and safety of nivolumab plus ipilimumab relative to other first-line therapies for advanced non-small-cell lung cancer: A systematic literature review and network meta-analysis.

OBJECTIVES: To quantify the long-term comparative efficacy and safety of nivolumab in combination with ipilimumab (NIVO + IPI) relative to other immunotherapy (IO)-based regimens and chemotherapy in patients with first-line advanced non-small cell lung cancer (aNSCLC). METHODS: Phase 3 randomized controlled-trials (RCTs) with minimum 3-year follow-up evaluating IO-based regimens approved for first-line aNSCLC were identified via systematic literature review. Analytic populations were defined by levels of PD-L1 expression and histology. Due to presence of proportional hazards violations, time-varying hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS) were estimated via Bayesian fractional polynomial network meta-analysis. For safety endpoints, odds ratios (ORs) were estimated using indirect treatment comparisons (ITCs). RESULTS: CheckMate 227, KEYNOTE-189, KEYNOTE-407, KEYNOTE-024, KEYNOTE-042, and IMpower150 were included in the base case analysis. For OS and PFS, HRs of NIVO + IPI relative to other IO-based regimens trended downward over time across analytic populations. The 36-month OS HRs of NIVO + IPI versus comparators were: 0.69 (95 % credible interval: 0.47, 1.00) versus pembrolizumab + chemotherapy and 0.65 (0.45, 0.93) versus atezolizumab + bevacizumab + chemotherapy in the non-squamous and PD-L1 all-comers population; 0.73 (0.53, 1.02) versus pembrolizumab + chemotherapy in the squamous and PD-L1 all-comers population; and 1.05 (0.83, 1.32) versus pembrolizumab in the mixed histology and PD-L1 ≥ 50 % population. For PFS, 36-month HR point estimates ranged from 0.46 to 0.85 (only statistically significant versus pembrolizumab + chemotherapy in the squamous population; 0.46 [0.31, 0.69]). Adverse events (AEs) leading to discontinuation were not statistically significantly different between NIVO + IPI and pembrolizumab + chemotherapy, nor between NIVO + IPI and pembrolizumab monotherapy, although treatment-related grade ≥ 3 AEs were higher with NIVO + IPI than pembrolizumab monotherapy (OR = 2.21 [1.30, 3.75]). CONCLUSIONS: This study indicates trends towards long-term benefit with NIVO + IPI compared with other IO-based combinations, with manageable toxicities.

Systematic review of outcomes and patient heterogeneity in relapsed or refractory diffuse large B-cell lymphoma.

Aim: To evaluate trials of systemic therapies in transplant-ineligible or -experienced, relapsed/refractory diffuse large-B cell lymphoma and the impact of patient characteristics on overall response rate (ORR). Patients & methods: Systematically reviewed multiple databases through 22 July 2021. Analyzed variations in patient characteristics and their relationship with ORR across trials. Results: Among 17 included trials, key patient characteristics varied substantially: primary refractory (0-69%), refractory to last line of therapy (LOT) (12-100%), ≥2 prior LOTs (14-100%), ≥3 prior LOTs (0-64%), IPI ≥3 (23-73%), tumor stage III/IV (50-90%) and median age (56-74 years). ORRs varied substantially (25-83%), correlating with these characteristics. Conclusion: Differences in patient characteristics significantly contribute to the variability in ORR across these trials and should be considered when contextualizing efficacy data.

Mirabegron and antimuscarinic use in frail overactive bladder patients in the United States Medicare population.

INTRODUCTION: Overactive bladder (OAB) and frailty are independently associated with patient burden. However, economic burden and treatment-taking behavior have not been well characterized among frail patients with OAB, which, given the varying safety and tolerability profiles of available treatments, is crucial. OBJECTIVES: To assess costs, health care resource utilization, treatment-taking behavior (persistence and adherence) to OAB medication in older, frail OAB patients. METHODS: This was a retrospective cohort study using international business machines MarketScan Medicare Supplemental claims data. Eligible frail patients (per Claims-based Frailty Index score) initiating mirabegron were 1:2 propensity score matched (based on age, sex, and other characteristics) with those initiating antimuscarinics and were followed up to 1 year. All-cause, per-person, per-month costs, health care encounters, persistence (median days to discontinuation assessed using Kaplan-Meier methods) and adherence (≥80% of proportion of days covered at Day 365) were compared. RESULTS: From 2527 patients with incident mirabegron (21%) or antimuscarinic (79%) dispensations, 516 incident mirabegron users (median age: 82 years, 64% female) were matched to 1032 incident antimuscarinic users (median age: 81 years, 62% female). Median cost was higher in mirabegron group ($1581 vs. $1197 per month); this was primarily driven by medication cost. There was no difference in medical encounters. Adherence (39.1% vs. 33.8%) and persistence (103 vs. 90 days) were higher in mirabegron users. CONCLUSIONS: Among frail older adults with OAB, mirabegron use was associated with higher costs and potential improvements in treatment-taking behaviors, particularly with respect to treatment adherence, versus those initiating antimuscarinics.

Correlations between objective response rate and survival-based endpoints in first-line advanced non-small cell lung Cancer: A systematic review and meta-analysis.

INTRODUCTION: The study objective was to estimate the relationship between objective response and survival-based endpoints by drug class, in first-line advanced non-small cell lung cancer (aNSCLC). MATERIALS AND METHODS: A systematic literature review identified randomized controlled trials (RCTs) of first-line aNSCLC therapies reporting overall survival (OS), progression-free survival (PFS), and/or objective response rate (ORR). Trial-level and arm-level linear regression models were fit, accounting for inclusion of immunotherapy (IO)-based or chemotherapy-only RCT arms. Weighted least squares-based R2 were calculated along with 95% confidence intervals (CIs). For the main trial-level analysis of OS vs. ORR, the surrogate threshold effect was estimated. Exploratory analyses involved further stratification by: IO monotherapy vs. chemotherapy, dual-IO therapy vs. chemotherapy, and IO + chemotherapy vs. chemotherapy. RESULTS: From 17,040 records, 57 RCTs were included. In the main analysis, trial-level associations between OS and ORR were statistically significant in both the IO-based and chemotherapy-only strata, with R2 estimates of 0.54 (95% CI: 0.26-0.81) and 0.34 (0.05-0.63), respectively. OS gains associated with a given ORR benefit were statistically significantly larger within IO vs. chemotherapy comparisons compared to chemotherapy vs. chemotherapy comparisons (p < 0.001). Exploratory analysis suggested a trend by IO type: for a given change in ORR, 'pure' IO (IO monotherapy and dual-IO) vs. chemotherapy RCTs tended to have a larger OS benefit than IO + chemotherapy vs. chemotherapy RCTs. For ORR vs. PFS, trial-level correlations were strong in the IO-based vs. chemotherapy (R2 = 0.84; 0.72-0.95), and chemotherapy vs. chemotherapy strata (R2 = 0.69; 0.49-0.88). For OS vs. PFS, correlations were moderate in both strata (R2 = 0.49; 0.20-0.78 and R2 = 0.49; 0.23-0.76). CONCLUSION: The larger OS benefit per unit of ORR benefit in IO-based RCTs compared to chemotherapy-only RCTs provides an important addition to the established knowledge regarding the durability and depth of response in IO-based treatments.

A Method for Reconstructing Individual Patient Data From Kaplan-Meier Survival Curves That Incorporate Marked Censoring Times.

Introduction. Access to individual patient data (IPD) can be advantageous when conducting cost-effectiveness analyses or indirect treatment comparisons. While exact times of censoring are often marked on published Kaplan-Meier (KM) curves, an algorithm for reconstructing IPD from such curves that allows for their incorporation is presently unavailable. Methods. An algorithm capable of incorporating marked censoring times was developed to reconstruct IPD from KM curves, taking as additional inputs the total patient count and coordinates of the drops in survival. The reliability of the algorithm was evaluated via a simulation exercise, in which survival curves were simulated, digitized, and then reconstructed. To assess the reliability of the reconstructed curves, hazard ratios (HRs) and quantiles of survival were compared between the original and reconstructed curves, and the reconstructed curves were visually inspected. Results. No systematic differences were found in HRs and quantiles in the original versus reconstructed curves. Upon visual inspection, the reconstructed IPD provided a close fit to the digitized data from the published KM curves. Inherent to the algorithm, censoring times were incorporated into the reconstructed data exactly as specified. Conclusion. This new algorithm can reliably be used to reconstruct IPD from reported KM survival curves in the presence of extractable censoring times. Use of the algorithm will allow health researchers to reconstruct IPD more closely by incorporating censoring times exactly as marked, requiring as additional inputs the total patient count and coordinates of the drops in survival.

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.

Undertreatment of overactive bladder among men with lower urinary tract symptoms in the United States: A retrospective observational study.

AIMS: To characterize the epidemiology and treatment patterns of adult men (≥40 years) diagnosed with, or treated for, overactive bladder (OAB) and/or benign prostatic hyperplasia (BPH). METHODS: This retrospective observational study used data extracted from the IBM MarketScan Commercial Claims and Encounters database and the Medicare Supplemental Coordination of Benefits database. Men with BPH and/or OAB were identified and observed to assess treatment and diagnostic patterns. RESULTS: Within the entire study sample (N = 462 400), BPH diagnosis (61.5%) and BPH treatment (73.7%) were more common than the corresponding values for OAB (25.8% and 7.0%, respectively). Notably, among diagnosed individuals, the dispensation of a corresponding treatment was more likely in individuals diagnosed with BPH (183 672 out of 284 416 = 64.6%) compared with OAB (16 468 out of 119 236 = 13.8%). Among newly diagnosed and/or treated patients (n = 196 576), only 60.3% received treatment. Among treated patients, most experienced only a single type of treatment (93.4%), 6.6% went on to receive a secondary treatment and 3.5% a tertiary. The most common primary treatment was alpha-blocker monotherapy (76.9%) followed by tadalafil monotherapy (16.4%). Among those untreated at first diagnosis, the median time between diagnosis and treatment initiation was 128 days. CONCLUSIONS: Diagnosis and management of OAB among males are challenging given the inherent overlap in symptoms observed with BPH. Unsurprisingly, we found that BPH is diagnosed and treated more frequently than OAB; but the differences between diagnosis and treatment patterns for the two conditions highlight the potential undertreatment of OAB and misdirection of therapy for men with a combination of voiding and storage symptoms.

Management of Patients with Overactive Bladder in Brazil: A Retrospective Observational Study Using Data From the Brazilian Public Health System.

INTRODUCTION: In Brazil, current data on the use of healthcare resources to manage individuals with overactive bladder (OAB) are lacking. This study aimed to characterize contemporary treatment and the economic burden among patients with OAB managed under the Brazilian public health system (Sistema Único de Saúde [SUS]). METHODS: Population-based data from January to December of 2015 were acquired from Brazil's public health database. Adults at least 18 years of age with an ICD-10 diagnostic code for OAB within the period were included. Records of outpatient visits, hospitalizations, and onabotulinumtoxinA injections were used to calculate estimates of resource use and costs (in Brazilian reals [R$]) among those with OAB (frequency [%] and mean (standard deviation [SD]) as appropriate). Patient identifiers were not available, so a record linkage methodology was used to match medical encounters to individuals. Pharmacologic management of OAB was informed by government medication purchases available from the official Brazilian government databases. RESULTS: During 2015, 26,640 patients with OAB were identified. All cohort members had at least one outpatient visit and 15,349 (57.6%) were hospitalized. Of the study cohort, 10.0% visited a general practitioner (GP), 41.3% visited a specialist, and 52.0% visited other non-medical healthcare practitioners within the year. Mean (SD) healthcare costs among the study cohort totaled R$355 (R$866) per patient per year; and were R$291 (R$654), R$27 (R$130), R$27 (R$30), and R$11 (R$17) for hospitalizations, GP, specialist, and non-medical healthcare practitioner visits per patient per year, respectively. Regional analysis of reported government medication purchases suggested that access to OAB treatments is highly limited. CONCLUSIONS: High resource use and costs were estimated among patients with OAB managed within the SUS. These data provide a snapshot of the management of patients with OAB in Brazil, with the patients seeking treatment under SUS likely representing a more burdened subpopulation.

A review of published anticholinergic scales and measures and their applicability in database analyses.

BACKGROUND/OBJECTIVES: Available metrics for characterizing cumulative anticholinergic exposure over time may not be well suited for use across all US data sources. In this review, the properties of existing anticholinergic scales and measures were evaluated to determine their suitability for implementation in observational studies relying on administrative data. METHODS: A targeted literature review was conducted to identify available anticholinergic scales and measures. Suitability of the identified scales and measures for quantification of anticholinergic exposure was evaluated based on pre-defined criteria. Agreement between selected scales was characterized by the percentage overlap of included drugs and inter-scale Spearman's correlation of scores. RESULTS: Sixteen scales were identified; six were relevant and suitable for the quantification of anticholinergic exposure. When implemented on administrative data the Anticholinergic Drug Scale and Anticholinergic Cognitive Burden scale demonstrated the most agreement, with an inter-scale correlation coefficient of 0.82. Scale performance varied by outcome of interest, and underlying disease profile of the population of interest. Variability across the two measures ("average daily dose" and "cumulative dose") was observed, with neither considering both dose and anticholinergic potency in score calculations. CONCLUSIONS: Accurate quantification of anticholinergic burden is important in assessing relative risks versus benefits of prescribing anticholinergic medications. In this review, the Anticholinergic Drug Scale and the Anticholinergic Cognitive Burden scale and the average daily dose and cumulative dose measures, were determined to be well suited for the quantification of anticholinergic exposure, particularly in the context of administrative data analyses; however, methods to characterize anticholinergic burden through consideration of both anticholinergic dose and potency are needed.

An Evaluation of Longitudinal Measures of Anticholinergic Exposure for Application in Retrospective Administrative Data Analyses.

INTRODUCTION: As continuous exposure to anticholinergics has been associated with adverse outcomes, accurately measuring exposure is important. However, no gold standard measure is available, and the performance of existing measures has not been compared. Our objective was to compare the properties of the Cumulative Anticholinergic Burden (CAB) measure against two existing measures of anticholinergic exposure and to assess their compatibility for use in observational studies based on claims data. METHODS: The average daily dose, cumulative dose and CAB measures were evaluated on: the applicability for use with anticholinergic burden scales, the ability to consider duration and/or accumulation of exposure, and consideration of anticholinergic dose, potency, and residual effect. To calculate each measure empirically, Truven MarketScan claims data from 2012 to 2015 were analyzed. Cumulative anticholinergic exposure over 1-year post-enrollment was calculated for each measure using Anticholinergic Cognitive Burden scale scores. Median [interquartile range (IQR)] and ranges of measure scores, and Spearman's correlation coefficients between measures, were estimated. Due to the differing methods of calculation, the absolute values of each score cannot be compared. RESULTS: The properties of the different measures varied, with only the CAB considering both dose and theoretical potency. The cohort included 99,742 individuals (mean age = 73.1 years; 54.9% female). Among individuals prescribed anticholinergics (n = 55,969), 1-year median (IQR) scores based on average daily dose, cumulative dose and CAB measures were 0.9 (0.3-1.5), 16.9 (7.3-33.9) and 203 (68-500), respectively. Measures were highly inter-correlated (r2 = 0.74-0.83). CONCLUSIONS: Considering both potency and dose, the CAB may prove a more comprehensive measure of anticholinergic burden; however, additional research is necessary to demonstrate whether it has any association with relevant health-related outcomes. FUNDING: Astellas Pharma Global Development, Inc.

The Relative Efficacy and Safety of Mirabegron and OnabotulinumtoxinA in Patients With Overactive Bladder who Have Previously Been Managed With an Antimuscarinic: A Network Meta-analysis.

OBJECTIVE: To compare the efficacy and safety of mirabegron and onabotulinumtoxinA in the management of treatment-experienced patients with overactive bladder. METHODS: The network meta-analysis was based on evidence from a systematic literature review of randomized controlled trials and a post-hoc analysis of treatment-experienced subpopulations from mirabegron studies. RESULTS: Nineteen trials described in 21 publications were included. CONCLUSION: Overall, compared to mirabegron, there was some evidence that onabotulinumtoxinA was associated with improved outcomes, including reductions in the number of micturitions in a 24-hour period, and the number of incontinence episodes. However, mirabegron was associated with a lower risk of urinary tract infections compared with onabotulinumtoxinA.

Effects of calcimimetics on long-term outcomes in dialysis patients: literature review and Bayesian meta-analysis.

AIM: Randomized controlled trials (RCTs) with clinical outcomes are considered the gold standard for regulatory approval. However, by design they are only able to answer a small number of clinical questions. Other high-quality studies are required for clinical decision-making. The EVOLVE was the largest RCT, evaluating the effects of cinacalcet on clinical outcomes among adult patients receiving maintenance dialysis suffering from secondary hyperparathyroidism. While the EVOLVE trial did not reach its primary end point, imbalance in subjects' age at randomization and discontinuation rates are two of the reasons that the lack of mortality benefit is in question. We undertook a systematic literature review and Bayesian meta-analysis combining randomized and observational studies on the estimated effects of the oral calcimimetic cinacalcet on clinical outcomes including all-cause mortality, cardiovascular-related mortality, hospitalization for cardiovascular events, fracture and parathyroidectomy among patients on maintenance dialysis. METHODS: Data sources included MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials databases. RCTs and observational studies were included. Data extraction was completed by two authors independently and in duplicate determined the methodological quality of the studies and extracted data. RESULTS: Of 564 unique citations identified, 16 studies were included: six observational studies and ten RCTs. Four high-quality studies (two observational and two RCTs) were deemed suitable for meta-analysis. Results indicated a statistically significant reduction in the risk of death associated with cinacalcet (hazard ratio: 0.83; 95% credible interval: 0.78-0.89). CONCLUSION: The results of this meta-analysis indicate that treatment of secondary hyperparathyroidism with calcimimetic therapy may in fact reduce mortality among patients receiving maintenance dialysis. This finding provides justification for a well-designed and adequately powered randomized trial to definitively address the question.

Assessing the Relationship between Performance on the University of California Performance Skills Assessment (UPSA) and Outcomes in Schizophrenia: A Systematic Review and Evidence Synthesis.

OBJECTIVE: To perform a systematic review of the published literature to evaluate how functional capacity, as measured by the University of California at San Diego (UCSD) Performance-based Skills Assessment (UPSA), relates to other functional measures and real-world outcomes among individuals with schizophrenia. METHODS: The MEDLINE® and Embase® databases were searched to identify joint evaluations with UPSA and key functional outcomes (functional scale measures; generic or disease-specific, health-related quality of life [HRQoL]; or real-world outcomes [residential status; employment status]) in patients with schizophrenia. Pearson correlations were estimated between UPSA scores, HRQoL, other functional scale measures, and real-world outcomes, for outcomes described in at least six studies. RESULTS: The synthesis included 76 studies that provided 73 unique data sets. Quantitative assessment between the Specific Level of Function (SLOF) (n=18) scores and UPSA scores demonstrated a moderate borderline-significant correlation (0.45, p=0.06). Quantitative analysis of the relationship between the Global Assessment of Functioning (GAF) (n=11) and the Multidimensional Scale of Independent Functioning (MSIF) (n=6) scales revealed moderate and small nonsignificant Pearson correlations of -0.34 (p=0.31) and 0.12 (p=0.83), respectively. There was a small borderline-significant correlation between UPSA score and residential status (n=36; 0.31; p=0.08), while no correlation was found between UPSA score and employment status (n=19; 0.04; p=0.88). CONCLUSION: The SLOF was the most often used functional measure and had the strongest observed correlation with the UPSA. Although knowledge gaps remain, evidence from this review indicates that there is a quantitative relationship between functional capacity and real-world outcomes in individuals with schizophrenia.

A Network Meta-analysis Comparing Exenatide Once Weekly with Other GLP-1 Receptor Agonists for the Treatment of Type 2 Diabetes Mellitus.

INTRODUCTION: Exenatide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA), approved for treatment of type 2 diabetes mellitus (T2DM). There is limited direct evidence comparing the efficacy and tolerability of exenatide 2 mg once weekly (QW) to other GLP-1 RAs. A network meta-analysis (NMA) was conducted to estimate the relative efficacy and tolerability of exenatide QW versus other GLP-1 RAs for the treatment of adults with T2DM inadequately controlled on metformin monotherapy. METHODS: A systematic literature review was conducted to identify randomized controlled trials (RCTs) that investigated GLP-1 RAs (albiglutide, dulaglutide, exenatide, liraglutide, and lixisenatide) at approved doses in the United States/Europe, added on to metformin only and of 24 ± 6 weeks treatment duration. A Bayesian NMA was conducted. RESULTS: Fourteen RCTs were included in the NMA. Exenatide QW obtained a statistically significant reduction in glycated hemoglobin (HbA1c) relative to lixisenatide 20 µg once daily. No other comparisons of exenatide QW to other GLP-1 RAs were statistically significant for change in HbA1c. No statistically significant differences in change in weight, systolic blood pressure, risk of nausea or discontinuation due to adverse events were observed for exenatide QW versus other GLP-1 RAs. CONCLUSION: Exenatide QW demonstrated similar effectiveness and tolerability compared to other GLP-1 RAs, for the treatment of T2DM in adults inadequately controlled on metformin alone.

Incidence and Costs of Clostridium difficile Infections in Canada.

Background. Limited data are available on direct medical costs and lost productivity due to Clostridium difficile infection (CDI) in Canada. Methods. We developed an economic model to estimate the costs of managing hospitalized and community-dwelling patients with CDI in Canada. The number of episodes was projected based on publicly available national rates of hospital-associated CDI and the estimate that 64% of all CDI is hospital-associated. Clostridium difficile infection recurrences were classified as relapses or reinfections. Resource utilization data came from published literature, clinician interviews, and Canadian CDI surveillance programs, and this included the following: hospital length of stay, contact with healthcare providers, pharmacotherapy, laboratory testing, and in-hospital procedures. Lost productivity was considered for those under 65 years of age, and the economic impact was quantified using publicly available labor statistics. Unit costs were obtained from published sources and presented in 2012 Canadian dollars. Results. There were an estimated 37 900 CDI episodes in Canada in 2012; 7980 (21%) of these were relapses, out of a total of 10 900 (27%) episodes of recurrence. The total cost to society of CDI was estimated at $281 million; 92% ($260 million) was in-hospital costs, 4% ($12 million) was direct medical costs in the community, and 4% ($10 million) was due to lost productivity. Management of CDI relapses alone accounted for $65.1 million (23%). Conclusions. The largest proportion of costs due to CDI in Canada arise from extra days of hospitalization. Interventions reducing the severity of infection and/or relapses leading to rehospitalizations are likely to have the largest absolute effect on direct medical costs.

Economic burden of surgically confirmed endometriosis in Canada.

OBJECTIVE: To estimate the societal economic burden of illness caused by surgically confirmed endometriosis in Canada in 2009, including direct health care costs, lost productivity, and lost leisure time costs. METHODS: Using a cross-sectional design, direct health care resource use data were obtained from nine family physicians and nine gynaecologists from across Canada, who were experienced in the treatment of women with surgically confirmed endometriosis. Data on alternative treatments and health care providers, as well as work absenteeism, lost leisure time, and caregiver time were obtained from a convenience sample of 27 women with endometriosis treated at two gynaecology clinics in Alberta and Quebec. Unit costs were assigned to resource use items for treatment-seeking patients, and total costs for each resource use item were aggregated to estimate the societal costs of endometriosis in Canada in 2009, across all prevalent cases of surgically confirmed endometriosis. RESULTS: The estimated mean annual societal cost of endometriosis was $5,200 per patient (95% CI $3,700 to $7,100), with lost productivity and lost leisure time costs accounting for 78%. Extrapolating these figures yields an estimated total annual cost to Canadian society of $1.8 billion (95% CI $1.3 billion to $2.4 billion) attributable to surgically confirmed endometriosis in Canada. CONCLUSION: For some women, surgically confirmed endometriosis has a substantial negative impact that can result in suffering to the individual and her family, and lead to substantial productivity losses. Understanding the interplay between direct costs, lost productivity, and quality of life is critical for accurately identifying and evaluating effective treatments for this condition.

Fondaparinux versus Enoxaparin in non-ST-elevation acute coronary syndromes: short-term cost and long-term cost-effectiveness using data from the Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators (OASIS-5) trial.

BACKGROUND: The study aimed to compare the short-term costs and long-term cost-effectiveness of 2 antithrombotics, fondaparinux and enoxaparin, for non-ST-elevation acute coronary syndrome in the United States. METHODS: It was based on a large randomized trial of 20,078 patients Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators [OASIS-5] comparing the therapies in these patients. In OASIS-5, fondaparinux patients had about half the rate of major bleeding 9 days after randomization and at least as good clinical outcomes (death, myocardial infarction, major bleeding and stroke) after 6 months of follow-up. Health care resource use and clinical efficacy data from the trial were incorporated into a cost-effectiveness model as applied to a general US health care system both for the time horizon of the study (6 months) and over the longer term. RESULTS: The 180-day cost analysis indicates that fondaparinux would generate a cost saving of $547 per patient (95% CI $207-$924). Sensitivity analysis suggested that savings could vary between $494 and $733. When 180-day cost and clinical results were extrapolated to long-term cost-effectiveness, fondaparinux was dominant (less costly and more effective in terms of quality-adjusted life-years) under most scenarios. CONCLUSIONS: Fondaparinux is a more cost-effective antithrombotic agent than enoxaparin in non-ST-elevation acute coronary syndrome. This is true across the range of event risks seen in OASIS-5.