Safety data in randomised real-world evidence studies: Salford Lung Study learnings.

Evidence to support clinical decision making must be based on safety data that have been captured, analysed and interpreted in a robust and reliable way. Randomised real-world evidence (RRWE) studies provide the opportunity to evaluate the use of medicines in patients and settings representative of routine clinical practice. However, elements that underpin the design of RRWE studies can have a significant impact upon the analysis, interpretation and implications of safety data. In this narrative review, we use data from the Salford Lung Study; two prospective, 12-month, open-label, parallel-group, phase III randomised controlled trials conducted in primary care in the UK; to highlight the importance of capturing treatment modifications when attempting to evaluate safety events according to actual treatment exposure. We demonstrate that analysing safety data by actual treatment received (i.e. accounting for the treatment modifications that occur routinely in the primary care setting) provides additional insight beyond analysing according to randomised treatment strategy only. It is therefore proposed that understanding of safety data from RRWE trials can be optimised by analysing both by randomised group and by actual treatment received.

Patient and healthcare professional experiences of the Salford Lung Studies: qualitative insights for future effectiveness trials.

BACKGROUND: Randomized controlled trials (RCTs) conducted in the routine care setting provide the opportunity to better understand the effectiveness of new medicines but can present recruitment difficulties. An improved understanding of the challenges/opportunities for patient and healthcare professional (HCP) engagement in clinical research is needed to enhance participation and trial experience. In this study, we explored patient and HCP drivers for, and experiences of, participation in the Salford Lung Studies (SLS), and their views on future trial participation and the overall value of such trials. METHODS: This was a qualitative study set in Salford, UK, comprising patient telephone interviews (N = 10) and HCP advisory boards (one with general practitioners [GPs], one with practice managers [PMs]); all individuals had participated in the SLS. Semi-structured telephone interviews were recorded, transcribed and analysed thematically. Advisory board meetings were analysed based on transcriptions of audio recordings and field notes. RESULTS: For patients, key positive aspects of the SLS were the ease/convenience of study assessments and excellent relationships with study nurses. GPs and PMs considered the SLS to be well-organized and highlighted the value of research nurse support; they also described minor challenges relating to trial systems, initial financial strain on practices and staff turnover. All participants indicated that they were very likely to participate in future trials, citing a design closely aligned with routine care practice as essential. Several strategies to encourage trial participation were suggested, such as clearly communicating benefits to patients and ensuring flexible study assessments. CONCLUSIONS: Patients and HCPs had positive experiences of the SLS. The study design, closely aligned with routine care, was considered important to their high likelihood of participating in future trials. The experiences of patients and HCPs in the SLS provide valuable insights that will help inform future best practice in the design and conduct of future real-world effectiveness RCTs in primary care. The detailed first-hand experiences of HCPs will be of significant value to others considering engaging in clinical research and participating in effectiveness RCTs.

Impact of socioeconomic status on participation and outcomes in the Salford Lung Studies.

COPD and asthma prevalence is associated with socioeconomic status (or "deprivation"), yet deprivation is rarely considered in typical large-scale efficacy randomised controlled trials that recruit highly selected patient populations. In this post hoc analysis of the Salford Lung Studies in COPD and asthma (two 12-month, open-label, effectiveness randomised controlled trials conducted in UK primary care), we evaluated the impact of patient deprivation on clinical outcomes with initiating fluticasone furoate/vilanterol versus continuing usual care. Patients were categorised into deprivation quintiles based on postcode and a countrywide database of indices of deprivation, and trial outcomes by quintile were assessed. 52% of patients in the COPD study were included in the most deprived quintile, contrasting with 20% in the asthma study. Greater deprivation was associated with higher rates of primary/secondary healthcare contacts and costs. However, the treatment effect of fluticasone furoate/vilanterol versus usual care for primary (COPD: moderate/severe exacerbations; asthma: Asthma Control Test responders at week 24) and secondary/other (healthcare consumption, adherence, treatment modifications, study withdrawals, exacerbations, serious adverse events) outcomes was similar across deprivation quintiles. Our findings support the recruitment of participants from all socioeconomic strata to allow assessment of data generalisability to routine clinical practice.

Can medicines development improve outcomes in asthma and chronic obstructive pulmonary disease management by driving effectiveness?

Despite the availability of treatment guidelines and inhaled medications for asthma and chronic obstructive pulmonary disease (COPD), much remains to be done to lessen the burden of these respiratory diseases for patients. The challenge of selecting effective and efficacious drugs for patients is a key focus area for healthcare professionals. Here we discuss the concept of "drivers of effectiveness"- features of a medicine which may increase or decrease its effectiveness in the presence of real-world factors - and highlight the importance of considering these drivers in the early stages of drug development, and exploring their impact in carefully designed pragmatic trials. Using the Salford Lung Studies (SLS) in asthma and COPD as an illustrative example, we discuss various features of the inhaled corticosteroid/long-acting ß2-agonist combination, fluticasone furoate/vilanterol (FF/VI), as potential drivers of effectiveness that may have contributed to the improved patient outcomes observed with initiation of FF/VI versus continuation of usual care in the UK primary care setting.

Chronic obstructive pulmonary disease exacerbation episodes derived from electronic health record data validated using clinical trial data.

PURPOSE: To validate an algorithm for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) episodes derived in an electronic health record (EHR) database, against AECOPD episodes collected in a randomized clinical trial using an electronic case report form (eCRF). METHODS: We analyzed two data sources from the Salford Lung Study in COPD: trial eCRF and the Salford Integrated Record, a linked primary-secondary routine care EHR database of all patients in Salford. For trial participants, AECOPD episodes reported in eCRF were compared with algorithmically derived moderate/severe AECOPD episodes identified in EHR. Episode characteristics (frequency, duration), sensitivity, and positive predictive value (PPV) were calculated. A match between eCRF and EHR episodes was defined as at least 1-day overlap. RESULTS: In the primary effectiveness analysis population (n = 2269), 3791 EHR episodes (mean [SD] length: 15.1 [3.59] days; range: 14-54) and 4403 moderate/severe AECOPD eCRF episodes (mean length: 13.8 [16.20] days; range: 1-372) were identified. eCRF episodes exceeding 28 days were usually broken up into shorter episodes in the EHR. Sensitivity was 63.6% and PPV 71.1%, where concordance was defined as at least 1-day overlap. CONCLUSIONS: The EHR algorithm performance was acceptable, indicating that EHR-derived AECOPD episodes may provide an efficient, valid method of data collection. Comparing EHR-derived AECOPD episodes with those collected by eCRF resulted in slightly fewer episodes, and eCRF episodes of extreme lengths were poorly captured in EHR. Analysis of routinely collected EHR data may be reasonable when relative, rather than absolute, rates of AECOPD are relevant for stakeholders' decision making.

Benefit and safety of fluticasone furoate/vilanterol in the Salford Lung Study in chronic obstructive pulmonary disease (SLS COPD) according to baseline patient characteristics and treatment subgroups.

BACKGROUND: SLS COPD was the first open-label randomised controlled trial demonstrating a reduction in moderate/severe COPD exacerbations with once-daily inhaled fluticasone furoate/vilanterol (FF/VI) in everyday clinical practice. Here we report FF/VI effectiveness and safety in predefined patient subgroups. METHODS: Patients with COPD, exacerbation history, and receiving maintenance inhaler therapy, were randomised to initiate FF/VI 100/25 µg or continue usual care (UC) with 12 months' follow-up. Annual rates of moderate/severe exacerbations (primary outcome), selected secondary outcomes, and incidence of pneumonia serious adverse events of special interest (SAESI) were compared between randomisation groups across various patient subgroups/baseline treatment strata. SAESI rates by actual treatment were also assessed. RESULTS: Lower exacerbation rates were observed for FF/VI versus UC across all subgroups/strata, including ICS + LABA therapy subset (8.0% [0.1, 15.4]), except in patients without baseline airflow limitation (-0.5% [-29.8, 22.1]). Larger reductions compared to the overall analysis were observed for patients on ICS-containing regimens (excluding LAMA) before the study (15.6% [3.4, 26.3]), and with baseline CAT score <10 (25.3% [-0.4, 44.4]). Pneumonia SAESI rates were similar for FF/VI versus UC across all subgroups/strata, except the LABA, LAMA or LABA + LAMA stratum (incidence ratio 2.8 [0.9, 8.5]). SAESI rates were not increased for FF/VI versus other ICS + LABA. CONCLUSIONS: Initiating FF/VI versus continuing UC reduced exacerbation rates without increased pneumonia SAESI risk compared to other ICS-containing regimens and in various patient subgroups, consistent with primary study findings. FF/VI may be a therapeutic option for a broad population of COPD patients, including those with more severe disease.

Patient-reported outcomes with initiation of fluticasone furoate/vilanterol versus continuing usual care in the Asthma Salford Lung Study.

BACKGROUND: The Asthma Salford Lung Study demonstrated the effectiveness and safety of initiating once-daily inhaled fluticasone furoate/vilanterol (FF/VI) versus continuing usual care (UC) in asthma patients in UK primary care [1]. Here, we report a detailed analysis of patient-reported outcome (PRO) endpoints. METHODS: Adults with symptomatic asthma maintained on inhaled corticosteroids (ICS) ±â€¯long-acting beta2-agonists (LABA) were randomized 1:1 to initiate FF/VI (100 [200]/25 µg) or continue UC. PROs were measured using the Asthma Control Test (ACT), Standardized Asthma Quality of Life Questionnaire (AQLQ [S]), Work Productivity and Activity Impairment: asthma questionnaire, and EQ-5D-3L (EuroQol 5-Dimensions 3-Levels) questionnaire, at timepoints across the 12-month study period. RESULTS: The individual components of ACT response (total score ≥20 or improvement from baseline ≥3) both contributed to the composite primary effectiveness endpoint at Week 24, with odds ratios favoring FF/VI over UC in both cases. Patients initiating FF/VI versus continuing UC were more likely to maintain/improve asthma control, regardless of baseline control status. The odds of patients being responders on AQLQ (S) total score and on individual AQLQ domains at Week 52 were significantly higher for FF/VI versus UC (all p < .001). FF/VI was associated with significantly greater reductions in overall work and activity impairment due to asthma (both p < .001), and a significantly greater change from baseline in EQ visual analogue scale score (p = .007), versus UC at Week 52. PRO findings were consistent across baseline ICS and ICS/LABA subsets. CONCLUSIONS: Initiation of FF/VI versus continuing UC was associated with consistent improvements in PROs.

Trabecular Anisotropy in the Primate Mandibular Condyle Is Associated with Dietary Toughness.

Past attempts to establish a relationship between mandibular morphology and different dietary categories (e.g., frugivore, folivore, insectivore) have had mixed results, possibly because descriptive dietary categories are too broad and obscure variation within primate diets. Another potential reason is that not all aspects of skeletal architecture, especially trabecular anisotropy, have factored into functional assessments of dietary inputs into jaw form. Recent emphasis on quantifying food mechanical properties (FMPs) has provided an alternative to reliance on dietary categories. We used data on FMPs to test for correlations among dietary toughness and Young's modulus and the trabecular structure of the mandibular condyle, which is loaded during feeding and should reflect differences in masticatory stresses associated with different dietary FMPs. Adult primate mandibles from 11 species were imaged using high-resolution X-ray computed tomography, and trabecular structure was analyzed with BoneJ and Quant3D to assess common three-dimensional trabecular parameters. Results of phylogenetic generalized least squares analysis suggested a positive correlation between the degree of anisotropy (DA) and toughness, and weaker correlations between FMPs and various other trabecular variables. Because the DA contributes to the mechanical properties of bone, these results suggest a functional relationship between dietary toughness and trabecular anisotropy in the mandibular condyle. Such a perspective underscores the need to consider all aspects of skeletal morphology in evaluating the links between diet and jaw biomechanics. Anat Rec, 2018. © 2018 Wiley Periodicals, Inc.

Effectiveness versus efficacy trials in COPD: how study design influences outcomes and applicability.

Guidelines for chronic obstructive pulmonary disease (COPD) management are based largely on results from double-blind randomised controlled trials (RCTs) of efficacy. These trials have high internal validity and test whether a drug is efficacious, but they are conducted in highly selected populations that may differ significantly from patients with COPD seen in routine practice.We compared the baseline characteristics, healthcare use and outcomes between the Salford Lung Study (SLS), an open-label effectiveness RCT, with six recent large-scale efficacy RCTs. We also calculated the proportion of SLS patients who would have been eligible for inclusion in an efficacy RCT by applying the inclusion criteria used in efficacy trials of combination treatments.SLS patients were older, included more females and more current smokers, had more comorbidities (including asthma), and had more often experienced exacerbations prior to inclusion. In the SLS, rates of moderate or severe exacerbations, incidence of overall serious adverse events (SAEs), and SAEs of pneumonia were more frequent. A maximum of 30% of patients enrolled in the SLS would have been eligible for a phase IIIa regulatory exacerbation study.Patients in large COPD efficacy RCTs have limited representativeness compared with an effectiveness trial. This should be considered when interpreting efficacy RCT outcomes and their inclusion into guidelines.

Effectiveness of fluticasone furoate plus vilanterol on asthma control in clinical practice: an open-label, parallel group, randomised controlled trial.

BACKGROUND: Evidence for management of asthma comes from closely monitored efficacy trials done in highly selected patient groups. There is a need for randomised trials that are closer to usual clinical practice. METHODS: We did an open-label, randomised, controlled, two-arm effectiveness trial at 74 general practice clinics in Salford and South Manchester, UK. Patients aged 18 years or older with a general practitioner's diagnosis of symptomatic asthma and on maintenance inhaler therapy were randomly assigned to initiate treatment with a once-daily inhaled combination of either 100 µg or 200 µg fluticasone furoate with 25 µg vilanterol or optimised usual care and followed up for 12 months. The primary endpoint was the percentage of patients who achieved an asthma control test (ACT) score of 20 or greater or an increase in ACT score from baseline of 3 or greater at 24 weeks (termed responders), in patients with a baseline ACT score less than 20 (the primary effectiveness analysis population). All effectiveness analyses were done according to the intention-to-treat principle. This study is registered with ClinicalTrials.gov, number NCT01706198. FINDINGS: Between Nov 12, 2012, and Dec 16, 2016, 4725 patients were enrolled and 4233 randomly assigned to initiate treatment with fluticasone furoate and vilanterol (n=2114) or usual care (n=2119). 1207 patients (605 assigned to usual care, 602 to fluticasone furoate and vilanterol) had a baseline ACT score greater than or equal to 20 and were thus excluded from the primary effectiveness analysis population. At week 24, the odds of being a responder were higher for patients who initiated treatment with fluticasone furoate and vilanterol than for those on usual care (977 [71%] of 1373 in the fluticasone furoate and vilanterol group vs 784 [56%] of 1399 in the usual care group; odds ratio [OR] 2·00 [95% CI 1·70-2·34], p<0·0001). At week 24, the adjusted mean ACT score increased by 4·4 points from baseline in patients initiated with fluticasone furoate and vilanterol, compared with 2·8 points in the usual care group (difference 1·6 [95% CI 1·3-2·0], p<0·0001). This result was consistent for the duration of the study. Pneumonia was uncommon, with no differences between groups; there was no difference in other serious adverse events between the groups. INTERPRETATION: In patients with a general practitioner's diagnosis of symptomatic asthma and on maintenance inhaler therapy, initiation of a once-daily treatment regimen of combined fluticasone furoate and vilanterol improved asthma control without increasing the risk of serious adverse events when compared with optimised usual care. FUNDING: GlaxoSmithKline.

Series: Pragmatic trials and real world evidence: Paper 3. Patient selection challenges and consequences.

This paper addresses challenges of identifying, enrolling, and retaining participants in a trial conducted within a routine care setting. All patients who are potential candidates for the treatments in routine clinical practice should be considered eligible for a pragmatic trial. To ensure generalizability, the recruited sample should have a similar distribution of the treatment effect modifiers as the target population. In practice, this can be best achieved by including-within the selected sites-all patients without further selection. If relevant heterogeneity between subgroups is expected, increasing the relative proportion of the subgroup of patients in the heterogeneous trial could be considered (oversampling) or a separate trial in this subgroup can be planned. Selection will nevertheless occur. Low enrollment and loss to follow-up can introduce selection and can jeopardize validity as well as generalizability. Pragmatic trials are conducted in clinical practice rather than in a dedicated research setting, which could reduce recruitment rates. However, if a trial poses a minimal burden to the physician and the patient and routine clinical practice is maximally adhered to, the participation rate may be high and loss to follow-up will not be a specific problem for pragmatic trials.

Hospital-acquired pressure injuries: The significance of the advanced practice registered nurse's role in a community hospital.

BACKGROUND AND PURPOSE: Hospital-acquired pressure injuries (HAPIs) continue to be a persistent problem in the acute care arena. The purpose of this retrospective quality improvement study was to examine if the introduction of nurse practitioners (NPs), as wound care consultants (WCCs), without other interventions, impacted the HAPI rates in a community hospital. METHODS: A retrospective, comparison design was used; 48 months of HAPI data (May 2010-2014) reported on the monthly National Database for Nursing Quality Indicators (NDNQI) survey was abstracted from hospital records. Data included the assessment of 10,752 patients and were divided into two groups for comparison: 24 months before and 24 months after NP hiring. CONCLUSIONS: There was a strong, inverse correlation between the presence of NPs and number of patients with HAPIs (r = -0.73, p < .01), indicating that HAPI rates were significantly lower after NPs took on the role of WCCs. The odds of a HAPI occurring following introduction of the NP WCCs were 20% of the odds in the previous years. IMPLICATIONS FOR PRACTICE: Study findings suggest that NPs assuming a leadership role as WCCs may be instrumental in decreasing HAPI rates.

Effectiveness of Fluticasone Furoate-Vilanterol for COPD in Clinical Practice.

BACKGROUND: Evidence for the management of chronic obstructive pulmonary disease (COPD) comes from closely monitored efficacy trials involving groups of patients who were selected on the basis of restricted entry criteria. There is a need for randomized trials to be conducted in conditions that are closer to usual clinical practice. METHODS: In a controlled effectiveness trial conducted in 75 general practices, we randomly assigned 2799 patients with COPD to a once-daily inhaled combination of fluticasone furoate at a dose of 100 µg and vilanterol at a dose of 25 µg (the fluticasone furoate-vilanterol group) or to usual care (the usual-care group). The primary outcome was the rate of moderate or severe exacerbations among patients who had had an exacerbation within 1 year before the trial. Secondary outcomes were the rates of primary care contact (contact with a general practitioner, nurse, or other health care professional) and secondary care contact (inpatient admission, outpatient visit with a specialist, or visit to the emergency department), modification of the initial trial treatment for COPD, and the rate of exacerbations among patients who had had an exacerbation within 3 years before the trial, as assessed in a time-to-event analysis. RESULTS: The rate of moderate or severe exacerbations was significantly lower, by 8.4% (95% confidence interval, 1.1 to 15.2), with fluticasone furoate-vilanterol therapy than with usual care (P=0.02). There was no significant difference in the annual rate of COPD-related contacts to primary or secondary care. There were no significant between-group differences in the rates of the first moderate or severe exacerbation and the first severe exacerbation in the time-to-event analyses. There were no excess serious adverse events of pneumonia in the fluticasone furoate-vilanterol group. The numbers of other serious adverse events were similar in the two groups. CONCLUSIONS: In patients with COPD and a history of exacerbations, a once-daily treatment regimen of combined fluticasone furoate and vilanterol was associated with a lower rate of exacerbations than usual care, without a greater risk of serious adverse events. (Funded by GlaxoSmithKline; Salford Lung Study ClinicalTrials.gov number, NCT01551758 .).

Primate dietary ecology in the context of food mechanical properties.

Substantial variation exists in the mechanical properties of foods consumed by primate species. This variation is known to influence food selection and ingestion among non-human primates, yet no large-scale comparative study has examined the relationships between food mechanical properties and feeding strategies. Here, we present comparative data on the Young's modulus and fracture toughness of natural foods in the diets of 31 primate species. We use these data to examine the relationships between food mechanical properties and dietary quality, body mass, and feeding time. We also examine the relationship between food mechanical properties and categorical concepts of diet that are often used to infer food mechanical properties. We found that traditional dietary categories, such as folivory and frugivory, did not faithfully track food mechanical properties. Additionally, our estimate of dietary quality was not significantly correlated with either toughness or Young's modulus. We found a complex relationship among food mechanical properties, body mass, and feeding time, with a potential interaction between median toughness and body mass. The relationship between mean toughness and feeding time is straightforward: feeding time increases as toughness increases. However, when considering median toughness, the relationship with feeding time may depend upon body mass, such that smaller primates increase their feeding time in response to an increase in median dietary toughness, whereas larger primates may feed for shorter periods of time as toughness increases. Our results emphasize the need for additional studies quantifying the mechanical and chemical properties of primate diets so that they may be meaningfully compared to research on feeding behavior and jaw morphology.

Employee Engagement and a Culture of Safety in the Intensive Care Unit.

A descriptive, retrospective design was used to explore the relationship between employee engagement and culture of safety in ICUs within a large Midwestern healthcare system. Results demonstrated a strong positive relationship between total engagement score and total patient safety score (r = 0.645, P < .01) and positive relationships between total engagement score and the 12 safety culture dimensions. These findings have implications for improving managerial strategies relative to employee engagement that may ultimately impact perceptions of a safety culture.

Nurses's knowledge of heart failure education principles.

OBJECTIVE: The goal of this study was to determine nurses' knowledge of heart failure (HF) self-management education principles. DESIGN: The study was exploratory and descriptive and included a convenience sample. SETTING: Research took place in a large midwestern health care system that included a university-based hospital, community hospitals, and home or palliative care. SUBJECTS: Subjects included 300 nurses who provide care to patients with HF. OUTCOME MEASURE: The outcome measures included overall and topic specific perceptions of basic information important to HF self-management. Topics included diet, fluids or weight, signs or symptoms of worsening condition, medications, and exercise. INTERVENTION: A 20-item, true or false written survey was administered between February 2000 and April 2000. RESULTS: Of the 300 nurses surveyed, 92% were registered nurses and 8% were licensed practical nurses; 38% worked in a large university-based hospital; 44% were employed at 5 community hospitals; and 18% worked in home or hospice-palliative care. Mean HF self-management knowledge score was 15.2 +/- 2.0. Registered nurses scored significantly higher than licensed practical nurses (15.3 vs 14.1; P =.004). Individual questions with overall scores <30% were related to dry or ideal weight in daily weight monitoring (24%), nonsymptomatic, low blood pressure (26%), and short-term dizziness when rising (19%). Individual question scores >30% and < or =75% were related to nonsteroidal anti-inflammatory inhibitor use (49%), potassium-based salt substitute use (52%), rest vs activity (72%), and lean delicatessen meat use in a low sodium diet (75%). In questions with scores <30%, nurses requested more information only 5% to 8% of the time. Overall analysis of variance indicated differences by work experience. HF nurses (primary population) scored higher than critical-care, medical-surgical, or telemetry floor nurses (16.2 +/- 1.7; 15.1 +/- 1.8; and 14.7 +/- 2.0, respectively; P <.001); home care nurses scored higher than hospital or palliative care nurses (15.9 +/- 1.5; 15.1 +/- 2.0; and 14.0 +/- 1.5, respectively; P =.006). CONCLUSION: Nurses may not be properly educated in HF self-management principles and must be provided with the right information so they can improve the quality and amount of information they offer to patients. Nurses who are better prepared to educate patients with HF may be more likely to carry out this nursing function as a part of their daily job role.