Shaun Holt

The global burden of asthma: executive summary of the GINA Dissemination Committee report

It is estimated that as many as 300 million people of all ages, and all ethnic backgrounds, suffer from asthma and the burden of this disease to governments, health care systems, families, and patients is increasing worldwide. In 1989 the Global Initiative for Asthma (GINA) program was initiated in an effort to raise awareness among public health and government officials, health care workers, and the general public that asthma was on the increase. The GINA program recommends a management program based on the best available scientific evidence to provide effective medical care for asthma tailored to local health care systems and resources. Working in continued collaboration with leaders in asthma care from many countries, GINA sponsors World Asthma Day (first Tuesday in May) which has been extremely successful. A vast number of people have made a commitment to bring awareness about the burden of asthma to their local health care officials, and to implement programs of effective asthma care. Beginning in 2003, the theme of World Asthma Day has been the ‘‘Global Burden of Asthma.’’ GINA commissioned Professor Richard Beasley, Wellington, New Zealand (member, GINA Dissemination Committee) to provide available data on the burden of asthma. A summary of this report is provided in this publication; the full document with data sets for 20 different regions worldwide may be obtained from the GINA website (http://www.ginasthma.com). Professor Beasley and his colleagues obtained data on the burden of asthma from literature primarily published through the International StudyofAsthmaandAllergies in Childhood (ISAAC) and the European Community Respiratory Health Survey (ECHRS). Methodologies differ in these studies, and epidemiological data on asthma are very difficult to collect, as Professor Beasley carefully describes in his segment on ‘‘Methodological Issues.’’ Nonetheless, the full report provides a wealth of information, along with a large number of scientific references. The study regions have been grouped according to geographical, political, historical, and racial considerations based on official data from WHO, the United Nations (UN), and other sources, and to some extent, the availability of asthma epidemiological data within the study region. Using the United Nations World Population Prospect Population Database (http://esa.un.org/unpp) as a source within each region, all countries were included, and in some cases territories and dependencies if specific asthma epidemiological data were available. For simplicity some data from small territories have been omitted or lumped in a larger sub-regional unit. The report will be updated as new information becomes available and following feedback from individual countries and regions. The GINA Executive Committee is indebted to Professor Beasley and his colleagues for providing this report that will be an invaluable source of information for those who wish to explore available data on the burden of asthma by region. It will be extremely useful to develop background materials for World Asthma Day activities in 2004 and well into the future. Matthew Masoli, Denise Fabian, Shaun Holt, Richard Beasley for the Global Initiative for Asthma (GINA) Program

Dose-response relation of inhaled fluticasone propionate in adolescents and adults with asthma: meta-analysis

Abstract Objective: To examine the dose-response relation of inhaled fluticasone propionate in adolescents and adults with asthma. Design: Meta-analysis of placebo controlled, randomised clinical trials that presented data on at least one outcome measure of asthma and that used at least two different doses of fluticasone. Setting: Medline, Embase, and GlaxoWellcomes internal clinical study registers. Main outcome measures: FEV1, morning and evening peak expiratory flow, night awakenings, β agonist use, and major exacerbations. Results: Eight studies, with 2324 adolescents and adults with asthma, met the inclusion criteria. Data on doses of >500 µg/day were limited. The dose-response curve for the raw data began to reach a plateau at around 100-200 µg/day and peaked by 500 µg/day. A negative exponential model for the data, without meta-analysis, indicated that 80% of the benefit at 1000 µg/day was achieved at doses of 70-170 µg/day and 90% by 100-250 µg/day. A quadratic meta-regression showed that the maximum achievable efficacy was obtained by doses of around 500 µg/day. The odds ratio for patients remaining in a study at a dose of 200 µg/day, compared with higher doses, was 0.73 (95% confidence interval 0.49 to 1.08). Comparison of the standardised difference in FEV1 for an inhaled dose of 200 µg/day against higher doses showed a difference in FEV1 of 0.13 of a standard deviation (−0.02 to 0.29). Conclusions: In adolescent and adult patients with asthma, most of the therapeutic benefit of inhaled fluticasone is achieved with a total daily dose of 100-250 µg, and the maximum effect is achieved with a dose of around 500 µg/day. However, these findings were limited by the lack of data on individual patients and by the paucity of dose-response studies that included doses of >500 µg/day. What is already known on this topic Inhaled corticosteroids are recommended for most patients with asthma, with the dose being increased as required to obtain control A therapeutic dose range of fluticasone propionate of 200-2000 µg/day is recommended in the British National Formulary for adults with asthma What this study adds Published data are insufficient to determine with confidence the dose-response relation of inhaled fluticasone at doses of >500 µg/day The dose-response curve for inhaled fluticasone in moderate to severe asthma in adolescents and adults, for all major clinical outcome measures, including exacerbations, begins to plateau at 100-200 µg/day and peaks at around 500 µg/day This study partially explains why adding a long acting β agonist to inhaled corticosteroids is more efficacious than increasing the dose of inhaled steroid beyond this dose range

Dose-response relationship of inhaled budesonide in adult asthma: a meta-analysis.

The aim of this study was to examine the dose-response relationship of inhaled budesonide in adolescents and adults with asthma. A meta-analysis was carried out on placebo-controlled, randomised clinical trials, presenting data on at least one outcome measure of asthma and using at least two doses of budesonide, delivered by turbuhaler or metered-dose inhaler+spacer twice daily. A total of six studies of 1,435 adolescents and adults, with mild to moderately severe asthma, met the inclusion criteria for the meta-analysis. A negative exponential model indicated that 80% of the benefit at 1,600 µg·day−1 was achieved at doses of ∼200–400 µg·day−1 and 90% by 300–600 µg·day−1. Meta-regression with a quadratic term in dose showed that the maximum effect was obtained with doses of ∼1,000 µg·day−1. In conclusion, the available published data indicate that, in adolescents and adults with mild to moderate asthma, most of the therapeutic benefit of budesonide delivered by turbuhaler or metered-dose inhaler+spacer is achieved with a dose of ∼400 µg·day−1 and the maximum effect is achieved at ∼1,000 µg·day−1. This conclusion is qualified by the recognition that there is considerable individual variability in the response to inhaled corticosteroids and that the subjects included in this meta-analysis had predominantly mild to moderate asthma.

Efficacy and safety of maintenance and reliever combination budesonide–formoterol inhaler in patients with asthma at risk of severe exacerbations: a randomised controlled trial

BACKGROUND The Single combination budesonide-formoterol inhaler Maintenance And Reliever Therapy (SMART) regimen reduces severe asthma exacerbations in patients, but whether the high doses of corticosteroid and β agonist increase the risk of adverse effects with both short-term and cumulative exposure is not certain. Our aim was to investigate whether the SMART regimen would reduce the risk of overuse of β agonist, reduce the likelihood of patients to seek medical review when such episodes occurred, and if any reduction in severe asthma exacerbations would be at the cost of a higher burden of systemic corticosteroid. METHODS In this 24-week trial undertaken at four primary health-care practices and one hospital in New Zealand, patients (aged 16-65 years) with a recent asthma exacerbation were randomly assigned in a 1:1 ratio to the SMART or standard fixed-dose regimen. Treatment in the SMART group consisted of two actuations of budesonide-formoterol (200 μg and 6 μg, respectively, per actuation) twice daily, delivered through a combination metered dose inhaler (MDI), with one extra actuation as needed for relief of symptoms; treatment in the standard group consisted of two actuations of budesonide-formoterol (200 μg and 6 μg, respectively, per actuation) twice daily through a combination MDI with one to two actuations of salbutamol (100 μg per actuation) by MDI as needed for relief of symptoms. MDIs were monitored electronically to measure actual use of medication. The allocation sequence for randomisation was computer generated, with a block size of eight per site. Participants, investigators, and the statistician were not masked to group assignment. The primary outcome was the proportion of participants with at least one high-use episode of β agonist (more than eight actuations per day of budesonide-formoterol in addition to the four maintenance doses in the SMART group or more than 16 actuations per day of salbutamol in the standard group). Analysis was by intention to treat. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12610000515099. FINDINGS 303 patients were randomly assigned to the SMART (n=151) or standard group (n=152). No significant difference was noted between the SMART and standard groups in the proportion of participants with at least one high-use episode of β agonist (84 [56%] vs 68 [45%], respectively, relative risk 1·24 [95% CI 0·99-1·56]; p=0·058). There were fewer days of high use in the SMART group (mean 5·1 days [SD 14·3] vs 8·9 days [20·9], relative rate 0·58 [0·39-0·88]; p=0·01). Of the patients who had at least one high-use episode, those in the SMART group had fewer days of high use without medical review (8·5 days [17·8] vs 18·3 days [24·8], 0·49 [0·31-0·75]; p=0·001). The SMART regimen resulted in higher inhaled corticosteroid exposure (943·5 μg budesonide per day [1502·5] vs 684·3 μg budesonide per day [390·5], respectively; ratio of means 1·22 [1·06-1·41]; p=0·006), but reduced oral corticosteroid exposure (77·5 mg prednisone [240·5] vs 126·6 mg prednisone [382·1], respectively; p=0·011), with no significant difference in composite systemic corticosteroid exposure (793·7 mg prednisone equivalent per year [893·1] vs 772·1 mg prednisone equivalent per year [1062·7], respectively; 1·03 [0·86-1·22]; p=0·76). Participants in the SMART group had fewer severe asthma exacerbations (35 [weighted mean rate per year 0·53] vs 66 [0·97]; relative rate 0·54 [0·36-0·82]; p=0·004). INTERPRETATION The SMART regimen has a favourable risk-to-benefit profile and can be recommended for use in adults at risk of severe asthma exacerbations. FUNDING Health Research Council of New Zealand.

Inhaled fluticasone propionate and adrenal effects in adult asthma: systematic review and meta-analysis

The dose–response relationship of inhaled fluticasone propionate (FP) for adrenal suppression in adults with asthma is not clear. The current authors carried out a systematic review and meta-analysis of placebo-controlled randomised dose–response studies of ≥4 weeks’ duration, which assessed the adrenal effects of FP by cosyntropin stimulation tests in adult asthma. The main outcome measure was the proportion of subjects with adrenal function below the lower limit of the normal range. Five studies, with a total of 732 subjects with asthma, met the inclusion criteria. Data on daily doses >1,000 μg were limited to one study. The proportion of subjects with adrenal function below the lower limit of the normal range on placebo was 3.9%; for a 500-μg per day increase in FP dose the odds of an abnormality increased by 1.38 (95% confidence interval 1.01–1.59). The continuous secondary outcome measures showed an inverse linear relationship with the FP dose up to 2,000 μg·day-1. In conclusion, for routine prescribing within the established therapeutic dose–response range (50–500 μg·day-1), fluticasone propionate has minimal effects on adrenal function. This conclusion is limited by the paucity of long-term studies of daily doses of fluticasone propionate >1,000 μg and by the considerable individual variability in the response.

Budesonide once versus twice‐daily administration: meta‐analysis

Objectives:  The aim of this study was to examine the efficacy of budesonide administered once daily compared to twice daily in asthma.

The pulmonary and extra-pulmonary effects of high-dose formoterol in COPD: a comparison with salbutamol.

Objectives:  Formoterol, a β2 agonist with a rapid onset of effect and long duration of action, can be used as maintenance and reliever medication for asthma and COPD. We compared the pulmonary and extra‐pulmonary effects of cumulative doses of formoterol and salbutamol in patients with COPD to assess efficacy and safety.

Design and baseline characteristics of participants in the Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial on the cardiovascular effects of dulaglutide

The aim was to determine the effects of dulaglutide, a synthetic once‐weekly, injectable human glucagon‐like peptide 1 analogue that lowers blood glucose, body weight, appetite and blood pressure, on cardiovascular outcomes. People with type 2 diabetes, aged ≥50 years, with glycated haemoglobin (HbA1c) ≤9.5%, and either a previous cardiovascular event, evidence of cardiovascular disease or ≥2 cardiovascular risk factors were randomly allocated to a weekly subcutaneous injection of either dulaglutide (1.5 mg) or placebo and followed within the ongoing Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial every 3 to 6 months. The primary cardiovascular outcome is the first occurrence of the composite of cardiovascular death or non‐fatal myocardial infarction or non‐fatal stroke. Secondary outcomes include each component of the primary composite cardiovascular outcome, a composite clinical microvascular outcome comprising retinal or renal disease, hospitalization for unstable angina, heart failure requiring hospitalization or an urgent heart failure visit, and all‐cause mortality. Follow‐up will continue until the accrual of 1200 confirmed primary outcomes. Recruitment of 9901 participants (mean age 66 years, 46% women) occurred in 370 sites located in 24 countries over a period of 2 years. The mean duration of diabetes was 10 years, mean baseline HbA1c was 7.3%, and 31% had prior cardiovascular disease. The REWIND trials international scope, high proportion of women, high proportion of people without prior cardiovascular disease and inclusion of participants whose mean baseline HbA1c was 7.3% suggests that its cardiovascular and safety findings will be directly relevant to the typical middle‐aged patient seen in general practice throughout the world.

Metered dose inhalers: A need for dose counters

Objectives:  This study investigated the ability of patients to assess when a metered dose inhaler (MDI) is empty.

Effect of smoking status on the efficacy of the SMART regimen in high risk asthma

The optimal management of people with asthma with a significant smoking history is uncertain. The aim of this study was to determine whether the efficacy/safety profile of single combination inhaled corticosteroid (ICS)/long acting beta‐agonist (LABA) inhaler maintenance and reliever therapy is influenced by smoking status.