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With increasing choice of medications and devices for asthma and chronic obstructive pulmonary disease (COPD) treatment, comparative evidence may inform treatment decisions. This systematic literature review assessed clinical and economic evidence for using a single combination inhaler versus multiple inhalers to deliver the same medication for patients with asthma or COPD. In 2016, Embase, PubMed and the Cochrane library were searched for publications reporting studies in asthma or COPD comparing a single-inhaler combination medicine with multiple inhalers delivering the same medication. Publications included English-language articles published since 1996 and congress abstracts since 2013. Clinical, economic and adherence endpoints were assessed. Of 2031 abstracts screened, 18 randomized controlled trials (RCTs) in asthma and four in COPD, nine retrospective and three prospective observational studies in asthma, and four observational studies in COPD were identified. Of these, five retrospective and one prospective study in asthma, and two retrospective studies in COPD reported greater adherence with a single inhaler than multiple inhalers. Nine observational studies reported significantly (n=7) or numerically (n=2) higher rates of adherence with single- versus multiple-inhaler therapy. Economic analyses from retrospective and prospective studies showed that use of single-inhaler therapies was associated with reduced healthcare resource use (n=6) and was cost-effective (n=5) compared with multiple-inhaler therapies. Findings in 18 asthma RCTs and one prospective study reporting lung function, and six RCTs reporting exacerbation rates, showed no significant differences between a single inhaler and multiple inhalers. This was in contrast to several observational studies reporting reductions in healthcare resource use or exacerbation events with single-inhaler treatment, compared with multiple inhalers. Retrospective and prospective studies showed that single-inhaler use was associated with decreased healthcare resource utilization and improved cost-effectiveness compared with multiple inhalers. Lung function and exacerbation rates were mostly comparable in the RCTs, possibly due to study design.

Jeffrey Trocio,1 Virginia M Rosen,2 Anu Gupta,3 Oluwaseyi Dina,1 Lien Vo,4 Patrick Hlavacek,1 Lisa Rosenblatt5 1US Health Economics and Outcomes Research Pfizer Inc., New York, NY, USA; 2Health Economics and Outcomes Research, Optum Inc., Eden Prairie, MN, USA; 3US Medical Affairs, Pfizer Inc., New York, NY, USA; 4US Health Economics and Outcomes Research, Bristol-Myers Squibb, Lawrenceville, NJ, USA; 5US Medical Affairs, Bristol-Myers Squibb, Lawrenceville, NJ, USA Introduction: Direct oral anticoagulants (DOACs) have emerged as viable alternatives to traditional treatments such as vitamin K antagonists (VKAs) for venous thromboembolism (VTE). The objective of this review was to summarize evidence on the use of DOACs and VKAs to treat VTE in the US for patients transitioning from inpatient to post-discharge settings. Materials and methods: A systematic review of the VTE literature identified studies published in English (January 1, 2011–December 31, 2016) that reported inpatient and post-discharge treatments and discharge location. Two reviewers screened abstracts, abstracted information from included studies, and assessed the quality of the study methodology and reporting. Results: Forty-nine studies were included (24 clinical and 25 economic). A limited number of studies (eight clinical and three economic) examined VTE treatment patterns during transitions of care from inpatient to post-discharge settings, irrespective of anticoagulant (eg, DOAC, warfarin, heparin), and < 25% of all studies reported a post-discharge location. Three clinical studies that reported inpatient and outpatient treatment found better patient outcomes with DOAC vs warfarin. Fourteen economic studies reported that DOACs were associated with shorter hospital length of stay (LOS) and lower direct costs vs warfarin. No studies reported indirect costs. Discussion: Although DOACs are associated with shorter LOS, lower costs, and better patient outcomes vs VKAs, it appears in one study that only a small percentage of patients with stable VTE who are discharged to home may be receiving DOACs. Conclusion: These findings identified the potential areas of opportunity to improve the management of VTE through coordination of care from the inpatient to the outpatient settings. Keywords: deep vein thrombosis, pulmonary embolism, anticoagulant, transition of care

Supplemental digital content is available in the text., Objective Despite advances in cervical cancer prevention and diagnosis, outcomes for patients given a diagnosis of advanced and recurrent disease are poor. In the GOG240 trial, the addition of bevacizumab to paclitaxel-topotecan or paclitaxel-cisplatin has been shown to prolong survival compared with paclitaxel-topotecan or paclitaxel-cisplatin in patients with persistent, recurrent, or metastatic disease. However, standards of care vary between regions and countries. The purpose of this systematic review and network meta-analysis was to enable a comparison between bevacizumab + chemotherapy with multiple monotherapy or combination chemotherapy regimens in the treatment for women with advanced, recurrent, or persistent cervical cancer. Methods/Materials A systematic literature review was conducted to identify randomized or nonrandomized controlled trials of patients with recurrent, persistent, or metastatic cervical cancer published in English from 1999 to 2015. A feasibility study was performed to assess the heterogeneity of the trials, and a network meta-analysis was conducted. Fixed- and random-effects models were fitted to calculate the hazard ratio for overall survival (OS) for all pairwise comparisons and ranking of all interventions. Results Twenty-three studies (19 trials) met inclusion criteria and were included in the review. Sample sizes ranged from 69 to 452, and median patient age ranged from 45 to 53 years. There was a trend toward prolonged OS with cisplatin-paclitaxel-bevacizumab and topotecan-paclitaxel-bevacizumab compared with all non–bevacizumab-containing therapies. Cisplatin-paclitaxel-bevacizumab had the highest probability of being the most efficacious compared with all regimens (68.1%), and cisplatin monotherapy had the lowest (0%). Conclusions The results of this network meta-analysis show that bevacizumab in combination with paclitaxel-topotecan or paclitaxel-cisplatin is likely to prolong OS over other non–bevacizumab-containing chemotherapies (eg, paclitaxel-carboplatin), which were not included in the GOG240 trial. In patients with advanced, persistent, and recurrent cervical cancer, cisplatin-paclitaxel-bevacizumab and topotecan-paclitaxel-bevacizumab showed the highest efficacy in all regimens investigated in this analysis.

Objectives To estimate the budgetary impact of varenicline in the United Kingdom (UK) in the first 5 years after its introduction to the smoking-cessation aid market, from the National Health Service (NHS) pharmacy perspective. Methods The economic impact of varenicline to the national health budget is estimated in a population of current, former, and new smokers. The analyses are based on data from a variety of secondary sources including national health data, clinical trials, and meta-analyses of smoking-cessation aids. The number of patients seeking aid and the treatment patterns are estimated using 2004 national health surveys, costs for medications from national prescription drug pricing tariffs, and efficacy of the various smoking-cessation aids from clinical trial data. Sensitivity analyses were performed to evaluate the impact of varying the patient parameters and costs. Results Model estimates suggest that the budgetary impact of varenicline would be £3.6 million in the second year after its introduction, with a 95% confidence interval of £0.63 to £7.2 million, and a resultant increase of 0.05% to the total NHS pharmacy budget. The model predicts that the addition of varenicline to the market would result in an additional 162,000 successful smoking-cessation attempts and 103,000 fewer smokers over 5 years, when compared to the world without varenicline. Conclusion The introduction of varenicline is likely to result in greater numbers of individuals succeeding at smoking cessation, with an approximately £3.6 million (0.05%) increase in the NHS pharmacy budget.

To estimate overall rates of adherence, persistence, and discontinuation for patients with type 2 diabetes mellitus (T2DM) prescribed oral antihyperglycemic agents (OAHAs) by combining results of published studies.A systematic literature review was conducted to identify articles published in English over the last 10 years evaluating the use of OAHAs for the treatment of T2DM. Databases searched included PubMed/MEDLINE, EMBASE, and the Cochrane Library. Seventy studies reporting adherence, persistence or discontinuation were identified by two independent reviewers and 40 reported relevant endpoints for the analysis. Outcomes included: (1) mean adherence defined as the average medication possession ratio (MPR); (2) proportion of adherent patients (MPR ≥ 80%); (3) discontinuation; and (4) persistence. Adherence and persistence were reported in observational studies only. Discontinuation was examined separately in randomized controlled trials (RCTs) and observational studies. Meta-analyses were conducted using both fixed and random effects models. When meta-analysis was not appropriate for a given outcome, descriptive statistics were provided.The pooled mean MPR (95% confidence interval [CI]) was 75.3% (68.8%-81.7%; n = 13) and the proportion of adherent patients (95% CI) was 67.9% (59.6%-76.3%; n = 12). The discontinuation rate (95% CI) in RCTs was 31.8% (17.0%-46.7%; n = 7). Persistence and discontinuation were not assessed via meta-analysis for observational studies due to the limited number of available studies and differences in outcome definitions. In these studies, persistence estimates ranged from 41.0% to 81.1%, with a mean (95% CI) of 56.2% (46.1%-66.3%; n = 6), while discontinuation estimates ranged from 9.9% to 60.1%, with a mean (95% CI) of 31.4% (17.6%-45.3%; n = 6).Limitations include (1) the use of MPR as a proxy for adherence, (2) limited number of studies available, and (3) observed heterogeneity.The results of the analysis demonstrate that medication adherence, persistence, and discontinuation rates are suboptimal in patients with T2DM prescribed OAHAs.

Two groups of non-demented individuals, who differed on genetic risk for Alzheimer's disease (AD) based on their apolipoprotein E (APOE) genotype, were tested on a category fluency task. Twenty varepsilon4 carriers and twenty varepsilon4 non-carriers were tape recorded while saying animal names for ten minutes. Five measures were examined: total names generated; total clusters; mean cluster size; mean within-cluster retrieval time; and mean between-cluster retrieval time. Groups were matched on age and education and scored as normal on a battery of psychometric tests. The varepsilon4 carriers generated significantly fewer names and clusters, and took significantly longer to access clusters, when compared to the varepsilon4 non-carriers. No group differences were found for cluster size or within-cluster retrieval times. We previously reported [Rosen, V. M., Bergeson, J. L., Putnam, K., Harwell, A., Sunderland, T. (2002). Working memory and apolipoprotein E: What's the connection? Neuropsychologia 40, 2226-2233] that the varepsilon4 carriers in the present study scored significantly lower than the varepsilon4 non-carriers on a measure of working memory/attentional capacity [Operation Span Task, see Turner, M. L., Engle, R. W. (1989). Is working memory capacity task dependent? Journal of Memory and Language 28, 127-154]. In the present study, a significant negative relationship found between span performance and between-cluster retrieval times suggested that reduced attentional capacity may have negatively impacted semantic access for the varepsilon4 carriers. Finally, we found significant relationships between a Trail Making Test [Reitan, R. M. (1992). Trail Making Test, manual for administration and scoring. Tucson, AZ: Reitan Neuropsychology Laboratory] "switch" measure (Form B-Form A) and three of the five fluency measures. The findings suggested that the varepsilon4 carrier's reduced attentional capacity may have interfered with their covertly shifting attention among subcategories in the fluency task, resulting in fewer names and clusters generated and longer times to access clusters.

Background: Demonstrating improved overall survival (OS) with new multiple myeloma (MM) treatments is becoming difficult because of extended survival, so progression-free survival (PFS) is commonly used as a surrogate endpoint for OS. We evaluated PFS as a potential surrogate for OS by examining whether observed treatment effects on PFS are positively associated with treatment effects on OS in MM. Methods: A systematic literature review identified 21 randomized control trials reporting hazard ratios (HRs) for treatment effects on PFS and OS. Pearson's r estimated the relationship between HRs (HRPFS and HROS), and between log-transformed HRs (log(HRPFS) and log(HROS)). R2 values were estimated from linear regression models of the HR and the log(HR) relationships. Sensitivity and subgroup analyses examined the robustness of the HR findings. Results: Positive correlations were found between HRPFS and HROS (r = 0.82; p < 0.0001) and between log(HRPFS) and log(HROS) (r = 0.80; p < 0.0001). Linear regression models produced R2 values of 0.67 and 0.63 when regressing HROS on HRPFS, and log(HROS) on log(HRPFS), respectively. Sensitivity analyses supported the HR findings. Conclusion: This analysis provides evidence for a positive association between treatment effects on PFS and OS. Studies involving patient level data are necessary to confirm whether PFS is a valid surrogate for OS in MM.

Two experiments examined whether a relationship exists between an individual's working memory capacity and their ability to suppress intrusive thoughts and behaviors. In both experiments, participants learned three lists in a modified paired-associates task where the interference condition followed an AB–AC–AB design and the noninterference condition an EF–DC–AB design. Experiment 1 stressed speed, and individuals who scored high on a measure of working memory capacity (high spans) produced fewer first-list intrusions during second-list learning than did low spans. Experiment 2 stressed accuracy, and high spans in the interference condition were slower than their control to retrieve first-list responses on List 3, suggesting that they had suppressed them during second-list learning. In contrast, the low spans in the interference condition were faster than their control. The findings suggested that a relationship exists between an individual's working memory capacity and their ability to suppress intrusive thoughts and behaviors.

The present study examined whether forward and backward serial recall performance reflects different codes, or different levels of processing complexity. One hundred twenty-two participants saw sequences of 2 to 9 letters (phonologically similar or dissimilar) for 1 second each in the center of a computer screen, and recalled the letters in forward or backward order. Participants correctly recalled more when letters were phonologically dissimilar, and when recall direction was forward. No interaction was found between direction of recall and phonological similarity, which suggests that a phonological code was used for both forward and backward recall. Also, forward and backward recall did not differentially predict SAT performance, which suggests that forward and backward recall required a similar level of processing complexity.

The aim of the study was to determine whether the epsilon 4 allele of the apolipoprotein E (ApoE) gene was associated primarily with context-specific memory among individuals at genetic risk for developing Alzheimer's disease. The effect of ApoE status on comprehensive neuropsychological results was examined in 176 healthy adults during baseline cognitive testing in the NIMH Prospective Study of Biomarkers for Older Controls at Risk for Alzheimer's Disease (NIMH Prospective BIOCARD Study). The presence of the epsilon 4 allele was associated with significantly lower total scores on the Logical Memory II subtest of the Wechsler Memory Scale-Revised and percent of information retained after delay. Further analysis indicated the prose recall and retention effect was partially explained by a small subgroup of epsilon 4 homozygotes, suggesting a gradually progressive process that may be presaged with specific cognitive measures. The current results may represent an epsilon 4-associated breakdown between gist-related information and context-bound veridical recall. This relative disconnection may be understood in light of putative epsilon 4-related preclinical accumulation of Alzheimer pathology (tangles and plaques) in the entorhinal cortex (EC) and among frontal networks, as well as the possibility of less-efficient compensatory strategies.

Two robust findings in the Alzheimer's literature are that patients with Alzheimer's disease (AD) show executive function and primacy deficits. The present study examined whether we would find similar deficits when comparing two groups of middle-aged individuals who differed with respect to genetic risk for AD, based on their apolipoprotein E (APOE) genotype. All individuals were screened as normal on a battery of standardized cognitive measures. They were tested on the "Operation span task", which engages the central executive component of working memory [J. Exp. Psychol.: Gen. 128 (1999) 309, J. Exp. Psychol.: Gen. 126 (1997) 211, J. Mem. Language 39 (1998) 418] by dividing attention between processing math operations and remembering words. Individuals were grouped according to APOE genotype ( epsilon 4 carrier versus epsilon 4 non-carrier), matched on age and education, and their Total span and Primacy scores were compared. Despite having no overt symptoms of dementia or deficits on a series of standardized psychometric tests, the epsilon 4 carriers showed divided-attention and primacy deficits on the Operation span task, when compared to the epsilon 4 non-carriers. As a point of comparison, Primacy scores were extracted from the first trial of the "Buschke selective reminding task" [J. Verbal Learn. Verbal Behav. 12 (1973) 543] for these same individuals, and no group differences were found. The Buschke task is a list-learning task that does not require divided attention. These findings suggested that the epsilon 4 carriers were less able to divide their attention, when compared to the epsilon 4 non-carriers. The findings provide the first direct evidence for a relationship between APOE genotype and cognitive performance on measures of divided attention and primacy with non-demented individuals who showed no cognitive impairments on standardized measures.

Abstract 4241 Background: The primary goals in the development of new oncology therapies are treatments that improve quality of life and overall survival (OS). In recent years, advances in the treatment of multiple myeloma (MM) have led to improvements in OS. However, with improved treatment options and multiple rounds of therapy it is becoming an increasing challenge to demonstrate OS improvements in clinical trials. Thus, progression free survival (PFS) is widely used as a surrogate endpoint to demonstrate long term clinical benefit. However, to our knowledge, there has been very limited analysis of the association between treatment effects on PFS and treatment effects on OS in patients with multiple myeloma (MM). Purpose: To evaluate whether observed treatment effects on PFS are positively associated with treatment effects on OS in MM based on published data from clinical trials in patients with MM. Methods: A systematic literature review of MM identified 13 published clinical trials that reported HRs for the effects of treatment on PFS and separately on OS. The patients in 12 of the studies were previously untreated, and one study included patients with relapsed/refractory disease. The Pearson correlation coefficient (Pearson r) was used to estimate the association between the reported hazard ratios (HRPFS and HROS), as well as the log-transformed HRs (log(HRPFS) and log(HROS)), for the treatment effects on PFS and OS. Linear regression models were used to evaluate the relationship between the HR, and log(HR), of PFS and OS. A log transformation of the HRs for PFS and OS was used in order to minimize any skewness and normalize the data. R-squared values were estimated from the regression models. 95% Confidence intervals around the R-squared values were estimated using Olkin and Finn's approximation (I. Olkin and J. D. Finn, Psychological Bulletin, Vol 118(1), Jul 1995, 155–164) of the standard error and Student's T distribution. Sensitivity analyses included the estimation of additional weighted regression models to investigate the robustness of the R-squared estimates using two weighting methods. Individual study sample sizes were used as weights in one method to allocate more precision to studies with larger sample sizes. Estimates of the geometric mean of the variance of the HRs were also utilized as weights to account for the multi-directional error around the two HRs. The geometric mean estimates were calculated as the inverse of the product of the width of the two HRs. Results: Pearson r estimates between the HRs for the treatment effects on PFS and OS showed a strong positive correlation between HRPFS and HROS r=0.815 (CI: 0.53–0.93; p Conclusion: This analysis based on published MM clinical trial results indicate that treatment effects on PFS may be positively associated with treatment effects on OS. Further studies involving patient-level data would be necessary to confirm these results. Disclosures: Zhang: BMS: Employment. Cartier:OptumInsight: Consultancy. Rosen:BMS: Consultancy. Teitelbaum:Optum Insight was hired to do literature review: Employment. Bartlett:Bristol-Myers Squibb: Employment. Kroog:Bristol-Myers Squibb: Employment. Mukhopadhyay:BMS: Employment. Wagner:Bristol-Myers Squibb: Employment.