Leukotriene antagonists as first-line or add-on asthma-controller therapy.

BACKGROUND: Most randomized trials of treatment for asthma study highly selected patients under idealized conditions. METHODS: We conducted two parallel, multicenter, pragmatic trials to evaluate the real-world effectiveness of a leukotriene-receptor antagonist (LTRA) as compared with either an inhaled glucocorticoid for first-line asthma-controller therapy or a long-acting beta(2)-agonist (LABA) as add-on therapy in patients already receiving inhaled glucocorticoid therapy. Eligible primary care patients 12 to 80 years of age had impaired asthma-related quality of life (Mini Asthma Quality of Life Questionnaire [MiniAQLQ] score ≤6) or inadequate asthma control (Asthma Control Questionnaire [ACQ] score ≥1). We randomly assigned patients to 2 years of open-label therapy, under the care of their usual physician, with LTRA (148 patients) or an inhaled glucocorticoid (158 patients) in the first-line controller therapy trial and LTRA (170 patients) or LABA (182 patients) added to an inhaled glucocorticoid in the add-on therapy trial. RESULTS: Mean MiniAQLQ scores increased by 0.8 to 1.0 point over a period of 2 years in both trials. At 2 months, differences in the MiniAQLQ scores between the two treatment groups met our definition of equivalence (95% confidence interval [CI] for an adjusted mean difference, -0.3 to 0.3). At 2 years, mean MiniAQLQ scores approached equivalence, with an adjusted mean difference between treatment groups of -0.11 (95% CI, -0.35 to 0.13) in the first-line controller therapy trial and of -0.11 (95% CI, -0.32 to 0.11) in the add-on therapy trial. Exacerbation rates and ACQ scores did not differ significantly between the two groups. CONCLUSIONS: Study results at 2 months suggest that LTRA was equivalent to an inhaled glucocorticoid as first-line controller therapy and to LABA as add-on therapy for diverse primary care patients. Equivalence was not proved at 2 years. The interpretation of results of pragmatic research may be limited by the crossover between treatment groups and lack of a placebo group. (Funded by the National Coordinating Centre for Health Technology Assessment U.K. and others; Controlled Clinical Trials number, ISRCTN99132811.).

Features of asthma management: quantifying the patient perspective.

BACKGROUND: In the management of asthma, features of care important to patients may not be fully appreciated. This study quantifies the importance of different features of asthma management from the patient perspective. This may assist in the development of personalised management strategies. METHODS: We used the technique of discrete choice experiment (DCE). Patients over 18 years of age with asthma, prescribed and taking medicine at step 3 of the UK guidelines were recruited from 15 general (family) practices in three areas of the UK. 147 evaluable questionnaires were returned from a total of 348 sent out. The outcome measures were the relative importance to patients of features of asthma management and the impact of changes in asthma management, as measured by utility shift between the features tested. RESULTS: The largest shift in mean utility values was recorded in "number of inhalers" and "use of inhaled steroid". Use of a personal asthma action plan was ranked next highest. CONCLUSION: This study suggests that adults with moderate or severe asthma would trade some improvements in symptom relief in favour of, for example, simpler treatment regimens that use as few inhalers as possible and a lower dose of inhaled steroid.

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.

Stroke-Like Presentation Following Febrile Seizure in a Patient with 1q43q44 Deletion Syndrome.

Hemiconvulsion-hemiplegia-epilepsy syndrome (HHE) is a rare outcome of prolonged hemiconvulsion that is followed by diffuse unilateral hemispheric edema, hemiplegia, and ultimately hemiatrophy of the affected hemisphere and epilepsy. Here, we describe the case of a 3-year-old male with a 1;3 translocation leading to a terminal 1q43q44 deletion and a terminal 3p26.1p26.3 duplication that developed HHE after a prolonged febrile seizure and discuss the pathogenesis of HHE in the context of the patient's complex genetic background.

Cost effectiveness of leukotriene receptor antagonists versus inhaled corticosteroids for initial asthma controller therapy: a pragmatic trial.

BACKGROUND: Information is lacking on the relative effectiveness and cost effectiveness--in a primary-care setting--of leukotriene receptor antagonists (LTRAs) as an alternative to inhaled corticosteroids (ICS) for initial asthma controller therapy. OBJECTIVE: To compare the cost effectiveness of LTRAs versus ICS for patients initiating asthma controller therapy. METHODS: An economic evaluation was conducted alongside a 2-year, pragmatic, randomized controlled trial set in 53 primary-care practices in the UK. Patients aged 12-80 years with asthma and symptoms requiring regular anti-inflammatory therapy (n = 326) were randomly assigned to LTRAs (n = 162) or ICS (n = 164). The main outcome measures were the incremental costs per point improvement in the Mini Asthma Quality of Life Questionnaire, per point improvement in the Asthma Control Questionnaire and per QALY gained from the UK NHS and societal perspectives. RESULTS: Over 2 years, resource use was similar between the two treatment groups, but the cost to society per patient was significantly higher for the LTRA group, at pounds sterling 711 versus pounds sterling 433 for the ICS group (adjusted difference pounds sterling 204; 95% CI 74, 308) [year 2005 values]. Cost differences were driven primarily by differences in prescription drug costs, particularly study drug costs. There was a nonsignificant (imputed, adjusted) difference between treatment groups, favouring ICS, in QALYs gained at 2 years of -0.073 (95% CI -0.143, 0.010). Therapy with LTRAs was, on average, a dominated strategy, and, at a threshold for willingness to pay of pounds sterling 30,000 per QALY gained, the probability of LTRAs being cost effective compared with ICS was approximately 3% from both societal and NHS perspectives. CONCLUSIONS: There is a very low probability of LTRAs being cost effective in the UK, at 2005 values, compared with ICS for initial asthma controller therapy. TRIAL REGISTRATION: UK National Research Register N0547145240; Controlled Clinical Trials ISRCTN99132811.

Cost effectiveness of leukotriene receptor antagonists versus long-acting beta-2 agonists as add-on therapy to inhaled corticosteroids for asthma: a pragmatic trial.

BACKGROUND: Information is lacking on the relative effectiveness and cost effectiveness--in a real-life primary-care setting--of leukotriene receptor antagonists (LTRAs) and long-acting beta2 adrenergic receptor agonists (beta2 agonists) as add-on therapy for patients whose asthma symptoms are not controlled on low-dose inhaled corticosteroids (ICS). OBJECTIVE: To estimate the cost effectiveness of LTRAs compared with long-acting beta2 agonists as add-on therapy for patients whose asthma symptoms are not controlled on low-dose ICS. METHODS: An economic evaluation was conducted alongside a 2-year, pragmatic, randomized controlled trial set in 53 primary-care practices in the UK. Patients aged 12-80 years with asthma insufficiently controlled with ICS (n = 361) were randomly assigned to add-on LTRAs (n = 176) or long-acting beta2 agonists (n = 185). The main outcome measures were the incremental cost per point improvement in the Mini Asthma Quality of Life Questionnaire (MiniAQLQ), per point improvement in the Asthma Control Questionnaire (ACQ) and per QALY gained from perspectives of the UK NHS and society. RESULTS: Over 2 years, the societal cost per patient receiving LTRAs was pounds sterling 1157 versus pounds sterling 952 for long-acting beta2 agonists, a (significant, adjusted) increase of pounds sterling 214 (95% CI 2, 411) [year 2005 values]. Patients receiving LTRAs experienced a non-significant incremental gain of 0.009 QALYs (95% CI -0.077, 0.103). The incremental cost per QALY gained from the societal (NHS) perspective was pounds sterling 22,589 (pounds sterling 11,919). Uncertainty around this point estimate suggested that, given a maximum willingness to pay of pounds sterling 30,000 per QALY gained, the probability that LTRAs are a cost-effective alternative to long-acting beta2 agonists as add-on therapy was approximately 52% from both societal and NHS perspectives. CONCLUSIONS: On balance, these results marginally favour the repositioning of LTRAs as a cost-effective alternative to long-acting beta2 agonists as add-on therapy to ICS for asthma. However, there is much uncertainty surrounding the incremental cost effectiveness because of similarity of clinical benefit and broad confidence intervals for differences in healthcare costs. TRIAL REGISTRATION: UK National Research Register N0547145240; Controlled Clinical Trials ISRCTN99132811.

Efficient and persistent transduction of exocrine and endocrine pancreas by adeno-associated virus type 8.

Efficient delivery of therapeutic proteins into the pancreas represents a major obstacle to gene therapy of pancreatic disorders. The current study compared the efficiency of recombinant lentivirus and adeno-associated virus (AAV) serotypes 1, 2, 5, 8 vectors delivered by intrapancreatic injection for gene transfer in vivo. Our results indicate that lentivirus and AAV 1, 2, 8 are capable of transducing pancreas with the order of efficiency AAV8 >>AAV1 > AAV2 >/= lentivirus, whereas AAV5 was ineffective. AAV8 resulted in an efficient, persistent (150 days) and dose-dependent transduction in exocrine acinar cells and endocrine islet cells. Pancreatic ducts and blood vessels were also transduced. Extrapancreatic transduction was restricted to liver. Leukocyte infiltration was not observed in pancreas and blood glucose levels were not altered. Thus, AAV8 represents a safe and effective vehicle for therapeutic gene transfer to pancreas in vivo.

Rediscovery of natural products using genomic tools.

A screening methodology called 'genomic screening' was established to identify natural products that can regulate cellular gene expression. Application of genomic screening to Keishi-bukuryo-gan (KBG), a Japanese herbal medicine formulation, identified a previously unnoticed transcriptional effect by linoleic acid, a known KBG component. The approach opens up a possibility to develop cell-permeable molecular tools for functional genomics research and sets a stage to evaluate the potential of natural products for transcription therapies.

Accessibility, acceptability, and effectiveness in primary care of routine telephone review of asthma: pragmatic, randomised controlled trial.

OBJECTIVE: To determine whether routine review by telephone of patients with asthma improves access and is a good alternative to face to face reviews in general practices. DESIGN: Pragmatic, randomised controlled trial. SETTING: Four general practices in England. PARTICIPANTS: 278 adults who had not been reviewed in the previous 11 months. INTERVENTION: Participants were randomised to either telephone review or face to face consultation with the asthma nurse. MAIN OUTCOME MEASURES: Primary outcome measures were the proportion of participants who were reviewed within three months of randomisation and disease specific quality of life, as measured by the Juniper mini asthma quality of life questionnaire. Secondary outcome measures included the validated "short Q" asthma morbidity score, nursing care satisfaction questionnaire score, and length of consultation. RESULTS: Of 137 people randomised to telephone consultation, 101 (74%) were reviewed, compared with 68 reviewed (48%) of the 141 people in the surgery group, a difference of 26% (95% confidence interval 14% to 37%; P<0.001; number needed to treat 3.8). Three months after randomisation the two groups did not differ in the Juniper score (risk difference -0.07 (95% confidence interval -0.40 to 0.27) or in satisfaction with the consultation (risk difference -0.07 (-0.27 to 0.13)). Telephone consultations were on average 10 minutes shorter than reviews held in the surgery (mean difference 10.7 minutes (12.6 to 8.8; P<0.001)). CONCLUSIONS: Compared with face to face consultations in the surgery, telephone consultations enable more people with asthma to be reviewed, without clinical disadvantage or loss of satisfaction. A shorter duration means that telephone consultations are likely to be an efficient option in primary care for routine review of asthma.