Comparative Safety Profile of the Fixed-Dose Combination Corticosteroid and Long-acting ß2-Agonist Fluticasone Propionate/Formoterol Fumarate: A 36-Month Longitudinal Cohort Study in UK Primary Care.

OBJECTIVE: The inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA) fluticasone propionate/formoterol fumarate (FP/FORM; Flutiform®) has been available as fixed-dose combination (FDC) therapy for asthma patients aged ≥ 12 years in the UK since 2012. This post-authorisation safety study examined adverse outcomes and prescribing practices for FP/FORM and other FDC ICS/LABA therapies in a real-life clinical setting over 36 months. METHODS: Historical, longitudinal cohort database study using UK primary care data from the Clinical Practice Research Datalink (CPRD) database, for patients initiated on or switched to an FDC ICS/LABA (ENCePP study number: EUPAS12330). The main cohort was adults aged ≥ 18 years with asthma. The primary outcome was incidence of new adverse outcomes after initiation of ICS/LABA; hazard ratios (HRs) and 95% confidence intervals were estimated for FP/FORM versus other FDC ICS/LABAs using Cox regression models. RESULTS: A total of 241,007 patients with an FDC ICS/LABA prescription were identified. In the adult asthma cohort (N = 41,609), the incidence rate of new adverse outcomes [in 100 patient-years (py)] was significantly lower for FP/FORM (24.75) versus fluticasone/salmeterol metered-dose inhaler [8.86; HR 1.14 (1.04, 1.25)], fluticasone/salmeterol dry powder inhaler [31.19; HR 1.18 (1.08, 1.29)], budesonide/formoterol [25.16; HR: 1.13 (1.03, 1.25)] and beclometasone/formoterol [25.47; HR 1.14 (1.04, 1.25)]. The overall prescribing rate was lower for FP/FORM (13.85 per 1000/py) than licensed FDC ICS/LABA comparators (20.30-28.13 per 1000/py). Of those prescribed FP/FORM, 80.8% were adults with asthma and < 7% were prescribed FP/FORM "off-label". CONCLUSIONS: The results suggest that FP/FORM was associated with an overall lower adverse outcome rate than the licensed comparators.

Fractional exhaled nitric oxide as a predictor of response to inhaled corticosteroids in patients with non-specific respiratory symptoms and insignificant bronchodilator reversibility: a randomised controlled trial.

BACKGROUND: Chronic non-specific respiratory symptoms are difficult to manage. This trial aimed to evaluate the association between baseline fractional exhaled nitric oxide (FeNO) and the response to inhaled corticosteroids in patients with non-specific respiratory symptoms. METHODS: In this double-blind randomised placebo-controlled trial, we enrolled undiagnosed patients, aged 18-80 years, with cough, wheeze, or dyspnoea and less than 20% bronchodilator reversibility across 26 primary care centres and hospitals in the UK and Singapore. Patients were assessed for 2 weeks before being randomly assigned (1:1) to 4 weeks of treatment with extrafine inhaled corticosteroids (QVAR 80 µg, two puffs twice per day, equivalent to 800 µg per day beclomethasone dipropionate) or placebo. Randomisation was stratified by baseline FeNO measurement: normal (≤25 parts per billion [ppb]), intermediate (>25 tp <40 ppb), and high (≥40 ppb). The primary endpoint was change in Asthma Control Questionnaire (ACQ7) mean score. We used generalised linear modelling to assess FeNO as a predictor of response, estimating an interaction effect between FeNO and treatment on change in ACQ7. We did our primary and secondary analyses in the per-protocol set, which excluded patients with non-completion of the primary endpoint, non-compliance to treatment (ascertained by patient report), and study visits made outside the predefined visit windows. This study is registered on ClinicalTrials.gov, number NCT02294279. FINDINGS: Between Feb 4, 2015, and July 12, 2016, we randomly assigned 294 patients to extrafine inhaled corticosteroid treatment (n=148) or placebo (n=146). Following exclusions due to protocol violations, we analysed 214 patients (114 extrafine inhaled corticosteroids and 100 placebo). We observed a significant interaction between baseline FeNO and treatment group for every 10 ppb increase in baseline FeNO, with the change in ACQ7 greater in the extrafine inhaled corticosteroids group than in the placebo group (difference between groups 0·071, 95% CI 0·002 to 0·139; p=0·044). The most common adverse events were nasopharyngitis (18 [12%] patients in the treatment group vs 13 [9%] in the placebo group), infections and infestations (25 [17%] vs 21 [14%]), and respiratory, thoracic, and mediastinal disorders (13 [9%] vs 17 [12%]). INTERPRETATION: FeNO measurement is an easy and non-invasive tool to use in clinical practice in patients with non-specific respiratory symptoms to predict response to inhaled corticosteroids. Further research is needed to examine its role in patients with evidence of other airway diseases, such as chronic obstructive pulmonary disease. FUNDING: Sponsored by OPRI with partial funding by Circassia and study drugs provided by TEVA.

A Randomized Pragmatic Trial of Changing to and Stepping Down Fluticasone/Formoterol in Asthma.

BACKGROUND: Guidelines recommend reducing treatment in patients with well-controlled asthma after 3 months of stability. However, there is inadequate real-life data to guide physicians on therapy change in daily practice. OBJECTIVE: To assess asthma control after change to and step-down of fluticasone propionate/formoterol fumarate dihydrate (FP/FOR) in real-life patients. METHODS: In a randomized controlled, pragmatic, open-label trial, 225 well-controlled patients with asthma were randomized (1:2) to maintain high-dose fluticasone propionate/salmeterol xinafoate (FP/SAL, 1000/100 µg) or switch to FP/FOR (1000/40 µg) daily for 12 weeks (phase 1). One hundred sixteen patients stable on FP/FOR at week 12 were subsequently randomized (1:1) to maintain this therapy, or stepped down to FP/FOR (500/20 µg) daily for 12 weeks (phase 2). The primary end point was the 7-question Asthma Control Questionnaire (ACQ7) score. RESULTS: In phase 1, FP/FOR (1000/40 µg) (n = 126) was noninferior to FP/SAL (1000/100 µg) (n = 73) for ACQ7 (difference in means, -0.12; 95% CI, -0.32 to 0.09). In phase 2, FP/FOR (500/20 µg) (n = 52) was noninferior to FP/FOR (1000/40 µg) (n = 52) for ACQ7 (difference in means, 0.01; 95% CI, -0.20 to 0.22). There was no significant difference in exacerbation rate between the groups in either phase. However, 1 to 2 exacerbations in 12 months before phase 1 were associated with the occurrence of an exacerbation after step-down (P = .007). CONCLUSIONS: In patients with well-controlled asthma, a change from FP/SAL to FP/FOR did not compromise asthma control. Step-down of FP/FOR was well tolerated; however, in contrast to current guidelines, our data suggest caution in stepping down patients uncontrolled in the last 12 months. Larger step-down studies are required to confirm these findings.

Initiating or changing to a fixed-dose combination of Fluticasone propionate/Formoterol over Fluticasone propionate/Salmeterol: A real-life effectiveness and cost impact evaluation.

OBJECTIVE: Asthma has a substantial impact on quality of life and health care resources. The identification of a more cost-effective, yet equally efficacious, treatment could positively influence the economic burden of this disease. Fluticasone propionate/Formoterol (FP/FOR) may be as effective as Fluticasone Salmeterol (FP/SAL). We evaluated non-inferiority of asthma control in terms of the proportion of patients free from exacerbations, and conducted a cost impact analysis. METHODS: This historical, matched cohort database study evaluated two treatment groups in the Optimum Patient Care Research Database in the UK: 1) an FP/FOR cohort of patients initiating treatment with FP/FOR or changing from FP/SAL to FP/FOR and; 2) an FP/SAL cohort comprising patients initiating, or remaining on FP/SAL pMDI combination therapy. The main outcome evaluated non-inferiority of effectiveness (defined as prevention of severe exacerbations, lower limit of the 95% confidence interval (CI) of the mean difference between groups in patient proportions with no exacerbations is -3.5% or higher) in patients treated with FP/FOR versus FP/SAL. RESULTS: After matching 1:3, we studied a total of 2472 patients: 618 in the FP/FOR cohort (174 patients initiated on FP/FOR and 444 patients changed to FP/FOR) and 1854 in the FP/SAL cohort (522 patients initiated FP/SAL and 1332 continued FP/SAL). The percentage of patients prescribed FP/FOR met non-inferiority as the adjusted mean difference in proportion of no severe exacerbations (95%CI) was 0.008 (-0.032, 0.047) between the two cohorts. No other significant differences were observed except acute respiratory event rates, which were lower for patients prescribed FP/FOR (rate ratio [RR] 0.82, 95% CI 0.71, 0.94). CONCLUSIONS: Changing to, or initiating FP/FOR combination therapy, is associated with a non-inferior proportion of patients who are severe exacerbation-free at a lower average annual cost compared with continuing or initiating treatment with FP/SAL.

Middle-aged and mobility-limited: prevalence of disability and symptom attributions in a national survey.

BACKGROUND: Lower limb mobility disabilities are well understood in older people, but the causes in middle age have attracted little attention. OBJECTIVES: To estimate the prevalence of mobility disabilities among noninstitutionalized adults in England and to compare the disabling symptoms reported by middle-aged and older people. DESIGN: Cross-sectional data from the 2002 English Longitudinal Study of Ageing (ELSA). Mobility disability was identified by level of reported difficulty walking a quarter mile. PARTICIPANTS: Eleven thousand two hundred sixteen respondents aged 50 years and older living in private households in 2002. RESULTS: The prevalence of difficulty walking a quarter mile increases sharply with age, but even in the middle-aged (50 to 64 years age-group) 18% (95% confidence interval [CI]: 16% to 19%) of men and 19% (95% CI: 17% to 20%) of women reported some degree of difficulty. Of the 16 main symptoms reported as causing mobility disability in middle age, 2 dominated: pain in the leg or the foot (43%; 95% CI: 40% to 46%) and shortness of breath/dyspnea (21%; 95% CI: 18% to 23%). Fatigue or tiredness, and stability problems were cited by only 5% and 6%, respectively. These proportions were slightly different from those in the 65 to 79-year age group: 40%, 23%, 6%, and 8%, respectively. CONCLUSIONS: Mobility (walking) disabilities in the middle-aged are relatively common. The symptoms reported as causes in this age group differ little from those reported by older groups, and are dominated by lower limb pain and shortness of breath. More clinical attention paid to disabling symptoms may lead to disability reductions in later life.

Vitamin K prophylaxis for preterm infants: a randomized, controlled trial of 3 regimens.

OBJECTIVE: Preterm infants may be at particular risk from either inadequate or excessive vitamin K prophylaxis. Our goal was to assess vitamin K status and metabolism in preterm infants after 3 regimens of prophylaxis. METHODS: Infants <32 weeks' gestation were randomized to receive 0.5 mg (control) or 0.2 mg of vitamin K1 intramuscularly or 0.2 mg intravenously after delivery. Primary outcome measures were serum vitamin K1, its epoxide metabolite (vitamin K1 2,3-epoxide), and undercarboxylated prothrombin assessed at birth, 5 days, and after 2 weeks of full enteral feeds. Secondary outcome measures included prothrombin time and factor II concentrations. RESULTS: On day 5, serum vitamin K1 concentrations in the 3 groups ranged widely (2.9-388.0 ng/mL) but were consistently higher than the adult range (0.15-1.55 ng/mL). Presence of vitamin K1 2,3-epoxide on day 5 was strongly associated with higher vitamin K1 bolus doses. Vitamin K1 2,3-epoxide was detected in 7 of 29 and 4 of 29 infants from the groups that received 0.5 mg intramuscularly and 0.2 mg intravenously, respectively, but in none of 32 infants from group that received 0.2 mg intramuscularly. After 2 weeks of full enteral feeding, serum vitamin K1 was lower in the infants who received 0.2 mg intravenously compared with the infants in the control group. Three infants from the 0.2-mg groups had undetectable serum vitamin K1 as early as the third postnatal week but without any evidence of even mild functional deficiency, as shown by their normal undercarboxylated prothrombin concentrations. CONCLUSIONS: Vitamin K1 prophylaxis with 0.2 mg administered intramuscularly maintained adequate vitamin K status of preterm infants until a median age of 25 postnatal days and did not cause early vitamin K1 2,3-epoxide accumulation. In contrast, 0.2 mg administered intravenously and 0.5 mg administered intramuscularly led to vitamin K1 2,3-epoxide accumulation, possibly indicating overload of the immature liver. To protect against late vitamin K1 deficiency bleeding, breastfed preterm infants given a 0.2-mg dose of prophylaxis should receive additional supplementation when feeding has been established.

Mobility disability in the middle-aged: cross-sectional associations in the English Longitudinal Study of Ageing.

BACKGROUND: Mobility (locomotor) disability is an early marker of disability progression, health care utilisation and institutionalisation in older people. Whether mobility disability has different causes in the middle-aged has received limited attention. OBJECTIVES: To examine associations of mobility disability with sociodemographic, behaviour and disease status and to contrast these with associations in older groups. DESIGN: Cross-sectional interview data from the 2002 English Longitudinal Study of Ageing. Mobility status based on reported difficulty walking a quarter of a mile (402 m). PARTICIPANTS: A total of 11,392 community-living respondents aged 50 years and over. RESULTS: In the middle-aged, 8% (95% CI 7-9%) of women and 9% (95% CI 8-11%) of men reported having much difficulty or being unable to walk a quarter of a mile, equating to 787,000 (95% CI 700,000-831,000) people in England. Factors which at least doubled odds of mobility disability in the middle-aged were chronic obstructive lung disease, angina, stroke, recently treated cancer, comorbidity, lower limb and back pain. Factors associated with mobility disability in older groups were similar. Thirty-eight per cent of mobility disability in the middle-aged population was related to high levels of lower limb pain and 15% to high levels of back pain. CONCLUSIONS: Mobility disability in the middle-aged is relatively common. The associated conditions in the middle-aged are similar to those in older people. Lower limb and back pain make dominant population contributions to mobility disability. Prevention of later disability progression may require more attention being paid to mobility difficulties and its causes in the middle-aged.

Developing functional outcome measures for unilateral neglect: a pilot study.

Stroke patients may develop personal neglect, peripersonal neglect or both. Four new measures were tested in a sample of 42 right-handed inpatients (25 male; 17 female, median age 72 years). Participants removed keys from a rack, identified grocery items, washed their face, and cleaned a tray. Prior to this, they were classified as: no neglect (15), personal neglect (8), peripersonal neglect (7), and both personal and peripersonal neglect (12). The sensitivity and specificity of each new measure was determined by agreement with the classification. Test-retest reliability was determined using weighted kappa statistics or limits of agreement. Four occupational therapists (OTs) rated videos of the face and tray measures, and software was developed to measure objectively time spent and area covered on Face and Tray. Keys and Grocery had high specificity, good reliability but poor sensitivity. For the OTs' video ratings, there was good and moderate inter-rater reliability on Tray and Face respectively for area covered, but not time spent. Intra-rater reliability was also better for area than time on Tray. However, the validity of Face and Tray themselves is currently inadequate. A longitudinal study is proposed to modify the measures, increase their sensitivity and evaluate their ability to monitor change over time.

Performance of older adults on tests of cognitive estimation.

This study provides performance data for older adults on two existing tests of cognitive estimation ability (Cognitive Estimation Test [CET] and Temporal Judgement Test [TJT]) and a novel set of estimation questions (n-EQ) that make reference to familiar, everyday objects. It explores the relations between each of the three tests of estimation and verbal intelligence. The sample comprises 101 adults aged 55 years and over. Neither n-EQ nor TJT scores were associated with verbal IQ, but scores on the more established CET were. As well as providing performance data for older adults, this study confirms the limitations of existing measures of cognitive estimation. It is proposed that the novel questions devised for this study show promise as an assessment tool, and warrant further validation.

Antibody response to diphtheria-tetanus-pertussis immunization in preterm infants who receive dexamethasone for chronic lung disease.

OBJECTIVE: To study the effect of dexamethasone in preterm infants with chronic lung disease (CLD) on antibody response to routine immunization against diphtheria, tetanus, and pertussis (DTP). METHODS: Serum samples were obtained before and after immunization with DTP (Trivax-AD) from an unselected cohort of 93 preterm infants in the United Kingdom. Antibodies to diphtheria and tetanus and to 4 pertussis antigens (pertussis toxin, filamentous hemagglutinin, pertactin, and fimbrial agglutinogens 2 + 3) were measured by an enzyme-linked immunosorbent assay. Linear regression models were fitted to the natural log of antibody titers to compare the dexamethasone-treated and -untreated infants adjusting for potential risk factors. RESULTS: Sixty-seven (72%) of 93 infants received dexamethasone. Preimmunization geometric mean titers (GMTs) were comparable in both groups for all antibodies. The rise in GMT after immunization was reduced in the dexamethasone-treated group. Final GMT was significantly lower for tetanus, diphtheria, pertussis toxin, and fimbrial agglutinogens 2 + 3 but not for filamentous hemagglutinin or pertactin. Using the minimum protective titer of 0.01 IU/mL, there was no significant reduction in protection for diphtheria and tetanus in the dexamethasone-treated infants. Using the higher reference titer of 0.1 IU/mL, there was a 16% reduction in protection for diphtheria (95% confidence interval: 3%-27%) and a 9% reduction in protection for tetanus (95% confidence interval: -7% to 20%). CONCLUSIONS: The use of dexamethasone for CLD in preterm infants is associated with a reduction in antibody titer to routine immunization against diphtheria and tetanus. Antibody responses to 2 of 4 pertussis antigens are reduced, but the clinical significance of this observation is unclear. Protection against tetanus and diphtheria is not impaired when the lower reference value for protective antibody is used. On the basis of this study of UK preterm infants who were treated with dexamethasone for the management of CLD, we conclude that the current DTP immunization schedule is adequate and do not recommend additional booster protection against tetanus or diphtheria during early infancy. When diphtheria prevalence is increased, however, additional protection should be considered.