Henrik Svedsater

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 .).

Identifying heuristic choice rules in the Swedish premium pension scheme

We analyze choices of a randomly selected sample of 10,999 citizens in the Swedish premium pension scheme. The aim is to identify the presence of various heuristic choice rules commonly observed in human decision making. Evidence suggests the prevalence of a default bias, the use of a diversification heuristic, extremeness aversion, a home bias, and the use of a 1/n heuristic. In some cases, cognitive simplification or wishful thinking may underlie the use of these heuristics. In other cases, their use seems to be consistent with recommendations provided by the responsible authority.

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 practitioners 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 practitioners 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.

A randomised open-label cross-over study of inhaler errors, preference and time to achieve correct inhaler use in patients with COPD or asthma: Comparison of ELLIPTA with other inhaler devices

Errors in the use of different inhalers were investigated in patients naive to the devices under investigation in a multicentre, single-visit, randomised, open-label, cross-over study. Patients with chronic obstructive pulmonary disease (COPD) or asthma were assigned to ELLIPTA vs DISKUS (Accuhaler), metered-dose inhaler (MDI) or Turbuhaler. Patients with COPD were also assigned to ELLIPTA vs Handihaler or Breezhaler. Patients demonstrated inhaler use after reading the patient information leaflet (PIL). A trained investigator assessed critical errors (i.e., those likely to result in the inhalation of significantly reduced, minimal or no medication). If the patient made errors, the investigator demonstrated the correct use of the inhaler, and the patient demonstrated inhaler use again. Fewer COPD patients made critical errors with ELLIPTA after reading the PIL vs: DISKUS, 9/171 (5%) vs 75/171 (44%); MDI, 10/80 (13%) vs 48/80 (60%); Turbuhaler, 8/100 (8%) vs 44/100 (44%); Handihaler, 17/118 (14%) vs 57/118 (48%); Breezhaler, 13/98 (13%) vs 45/98 (46%; all P<0.001). Most patients (57–70%) made no errors using ELLIPTA and did not require investigator instruction. Instruction was required for DISKUS (65%), MDI (85%), Turbuhaler (71%), Handihaler (62%) and Breezhaler (56%). Fewer asthma patients made critical errors with ELLIPTA after reading the PIL vs: DISKUS (3/70 (4%) vs 9/70 (13%), P=0.221); MDI (2/32 (6%) vs 8/32 (25%), P=0.074) and significantly fewer vs Turbuhaler (3/60 (5%) vs 20/60 (33%), P<0.001). More asthma and COPD patients preferred ELLIPTA over the other devices (all P⩽0.002). Significantly, fewer COPD patients using ELLIPTA made critical errors after reading the PIL vs other inhalers. More asthma and COPD patients preferred ELLIPTA over comparator inhalers.

Ease of use of the ELLIPTA dry powder inhaler: data from three randomised controlled trials in patients with asthma

Maintenance therapies for asthma are typically delivered via handheld inhalers. Poor adherence to inhaled medications and incorrect inhaler technique are known to adversely affect outcomes in asthma, contributing to the continuing failure for many patients to achieve control despite the availability of effective therapies.1 The ELLIPTA dry powder inhaler (DPI) is a handheld inhaler with single-step activation, featuring a cover that is opened by the patient to uncover the mouthpiece and activate a dose2 (ELLIPTA is a trademark of the GlaxoSmithKline group of companies). The actuated dose is subsequently inhaled from the mouthpiece.2 The ELLIPTA DPI is used to deliver fluticasone furoate (FF), a new inhaled corticosteroid licensed in Europe in combination with vilanterol, a new long-acting β2-agonist, for asthma and chronic obstructive pulmonary disease and in development as a monotherapy for asthma. The aim of this analysis was to investigate patient perception of the ease of use, and investigator-reported competence in use, of the ELLIPTA DPI. We describe a sub-analysis of the ease of use and inhaler competence data in patients with asthma from three randomised, multicentre clinical trials of FF/vilanterol combination therapy (HZA106827 (100/25 μg) and/or FF monotherapy (FFA114496 (100, 200 μg); FFA115283 (50 μg); HZA106827 (100 μg)), in which the ELLIPTA DPI was used to deliver study medication (including placebo where applicable). Preliminary results have been published in abstract form.2 The primary clinical trial data are reported separately.3–5 Patients completed a questionnaire at week 4 of each trial, rating the ease of use of the inhaler and how easy it was to tell how many doses of medication were left in the inhaler. For both questions, patients selected their response from the following ordinal scale: very easy, easy, neutral, difficult, and very difficult. Investigators assessed, by observation, patients’ competence in using the ELLIPTA DPI following one demonstration of correct usage at randomisation, at week 2 and at week 4. Data were analysed and interpreted descriptively; no statistical inference was planned. A total of 1,050 asthma patients (Supplementary Appendix) participated in the trials. Of these, 94% completed the questionnaire. Patient-reported ease of use and investigator-reported inhaler use assessment findings for each of the three clinical trials, together with pooled results, are presented in Table 1. The findings of both assessments were similar across the three trials (Supplementary Appendix). Table 1 Summary of findings of ELLIPTA dry powder inhaler ease of use questionnaire and investigator assessment of inhaler technique for each study and when pooled together Overall, 65% of questionnaire respondents reported that the inhaler was very easy to use, and 94% reported that it was easy or very easy to use. Only 1% of patients reported that the inhaler was difficult or very difficult to use. Similarly, 74% reported that they found it very easy to tell how many doses of medication were left in the inhaler using the in-built numerical dose counter, and 96% found it easy or very easy. Less than 1% of patients found it difficult or very difficult to tell how many doses were left in the inhaler. At randomisation, investigators reported that 95% of patients used the inhaler correctly after the initial demonstration of correct usage at randomisation (week 0), and did not require additional instruction. A further 4% of patients were able to use the inhaler correctly at randomisation after one additional instruction. The most common error made at randomisation (before any additional instruction) was to open the cover incorrectly (20 (1.9%) of all patients), followed by inhaling the dose incorrectly (15 (1.4%)), unspecified reason (12 (1.1%)), and closing the cover incorrectly (3 (0.3%)). At week 2 and week 4, >99% of patients used the inhaler correctly; four (0.4%) patients made errors at week 2 and week 4, respectively (Supplementary Appendix). In all three studies, the majority of participants found the inhaler to be easy to use, and were observed to use the inhaler correctly following a single demonstration. The design of the inhaler and appropriateness of the delivery mechanism to the patient may boost patient satisfaction with the medication regimen and competence in device use.6 Patient preference data obtained from a separate interview-based study7 are consistent with our findings, suggesting that patients with asthma and chronic obstructive pulmonary disease generally perceive the ELLIPTA DPI positively and find it easy to use. A similar questionnaire has previously been used to assess comparative ease of use in asthma patients participating in randomised controlled trials, whose responses indicated that the DISKUS DPI is easier to use than DiskHaler.8,9 Similarly, our single-device study was conducted against the background of randomised, controlled clinical trials in which all patients were given clear instruction in correct use of the inhaler at randomisation. Such thorough instruction is unlikely to be replicated in real-world clinical practice;10 this could therefore be considered a limitation in interpretation of this study. The perceived and observed ease of use findings reported in this analysis suggest that the ELLIPTA DPI may have the potential to reduce inhaler-related handling errors and improve adherence; however, further studies are required to specifically assess these possibilities.

Effect of Inhaled Corticosteroid Therapy Step-Down and Dosing Regimen on Measures of Asthma Control

Background: Asthma guidelines recommend stepping down therapy to the lowest dose that maintains asthma control. Objective: We sought to evaluate the effect of dosing frequency and baseline patient and treatment-related factors on database markers of asthma control after inhaled corticosteroid (ICS) dose step-down. Methods: This retrospective observational study evaluated primary care patients (4-80 years old) with asthma prescribed twice-daily (BD) ICS (n=26,834) or ICS/long-acting β-agonist (LABA; n=20,814) for ≥ 1 year before ≥ 50% step-down in ICS dose, when they were switched to once-daily (QD) or remained on BD therapy. Study endpoints included exacerbations (oral corticosteroid prescription, unscheduled asthma-related hospital attendance, or general practice consultation for lower respiratory tract infection) and medication adherence. Results: Significant improvements in most endpoints were recorded during the year after step-down, as compared with the prior year (baseline). The proportion of patients with no exacerbation during the baseline year vs. the year after step-down was as follows (p<0.001 for all comparisons): QD ICS cohort (73% baseline vs. 81% after step-down); BD ICS cohort (67% vs. 77%); QD ICS/LABA cohort (60% vs. 64%); BD ICS/LABA cohort (55% vs. 65%). Adherence improved significantly after step-down for all cohorts, most markedly for QD cohorts; and the average daily ICS dose as consumed by patients was higher for all but the QD ICS/LABA cohort despite the reduction in prescribed dose. Factors predicting loss of asthma control after step-down for patients controlled at baseline in either or both ICS and ICS/LABA populations included obesity, smoking, comorbid rhinitis, comorbid gastroesophageal reflux disease, and, during the baseline year, ≥ 7 short-acting β-agonist prescriptions, mean consumed ICS dose of ≥ 800 μg/day, and ≥ 4 primary care consultations. Conclusion: Stepping down therapy is a valid management option and may improve asthma-related outcomes. Some improvements may result from increased adherence, particularly among patients switched to QD therapy.

Momentum trading, disposition effects and prediction of future share prices: an experimental study of multiple reference points in responses to short- and long-run return trends

Returns of equities tend to exhibit momentum in the short to medium term and reversals in the longer term. While presenting results partly supporting such findings, we demonstrate that investors rely on multiple reference points in their trading behaviour. In particular it is shown that the interaction between long- and short-run returns may have important explanatory value for investment decisions. Predictions of future stock prices furthermore tend to be positively biased when evaluated against trading patterns, while loss aversion may drive investors to sometimes act against their beliefs about market sentiments. Implications for market responses to price movements are discussed.

Measurement properties of an asthma symptom and rescue medication use diary

Abstract Introduction: Assessment of symptoms and rescue medication use are well-established endpoints for clinical trials evaluating asthma treatment. Objective: To evaluate the measurement properties of an asthma symptom and rescue medication use (ASRMU) diary for clinical trials involving asthma patients aged ≥12 years. Methods: Interviews with 35 patients were conducted to confirm the importance of key concepts in the ASRMU diary. Scores of symptom and rescue medication use were converted to symptom-free days (SFD) and rescue-free days (RFD). Test–retest reliability and equivalence (based on intra-class correlation coefficients [ICCs]) between paper-and-pencil and electronic (eDiary) versions were evaluated in a prospective study in 47 patients. Responsiveness of the ASRMU diary was evaluated through differences in percentage of SFD and of RFD by treatment group in eight asthma clinical trials that assessed inhaled corticosteroids (ICS) and long-acting β2-agonists (LABA), alone or in combination. A ninth placebo-controlled study calculated effect sizes. Minimal important differences (MID) were determined using anchor-based methods from two trials and by interviewing 11 patients. Results: Patient interviews supported content validity for the ASRMU diary. Test–retest reliability was acceptable for SFD (ICC:0.70–0.75), but varied for RFD (ICC:0.58–0.78). Paper-and-pencil and eDiary modes of administration were equivalent (SFD, ICC = 0.84; RFD, ICC = 0.70). ICS/LABA had the largest percentage of SFD and RFD, followed by monotherapy and then placebo. MIDs were 7.7–14.7% for SFD and 8.4–15.6% for RFD. Conclusions: The ASRMU diary captures the disease-specific concepts of greatest importance to asthma patients and provides important information for asthma diagnosis and treatment evaluation.

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) ± 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.

Effectiveness of fluticasone furoate/vilanterol versus fluticasone propionate/salmeterol on asthma control in the Salford Lung Study

Abstract Objective: The Asthma Salford Lung Study demonstrated the effectiveness of initiating once-daily fluticasone furoate/vilanterol (FF/VI) versus continuing usual care in asthma patients in UK primary care [1]. Here, we report a secondary analysis in a subset of patients with fluticasone propionate/salmeterol (FP/Salm) as their baseline intended maintenance therapy, to evaluate the relative effectiveness of initiating FF/VI versus continuing FP/Salm. Methods: Adults with symptomatic asthma were randomised to initiate FF/VI 100[200]/25 µg or continue FP/Salm. The Asthma Control Test (ACT), Asthma Quality of Life Questionnaire (AQLQ), Work Productivity and Activity Impairment Asthma questionnaire, severe exacerbations, salbutamol inhaler prescriptions and serious adverse events (SAEs) were recorded throughout the 12-month treatment period. Results: One thousand two hundred and sixty-four patients (FF/VI 646; FP/Salm 618) were included in this subset analysis; 978 had baseline ACT score <20 and were included in the primary effectiveness analysis (PEA) population. At week 24, odds of patients being ACT responders (total score ≥20 and/or improvement from baseline ≥3) were significantly higher with FF/VI versus FP/Salm (71% vs. 56%; odds ratio 2.03 [95% CI: 1.53, 2.68]; p < 0.001 [PEA]). Significant benefit with FF/VI versus FP/Salm was also observed for AQLQ responders, activity impairment due to asthma, exacerbation rates, and salbutamol inhalers prescribed. No significant between-group differences were observed for impairment while working or work absenteeism due to asthma. Conclusions: For patients in primary care, initiating FF/VI was significantly better than continuing with FP/Salm for improving asthma control and quality of life, and reducing asthma exacerbations, with no notable difference in SAEs. ClinicalTrials.gov: NCT01706198.