Prospective study of inhaled corticosteroid use, cardiovascular mortality, and all-cause mortality in asthmatic women

BACKGROUND: Therapy with inhaled corticosteroids (ICSs) decreases the risk of asthma exacerbations. Recent studies have suggested that ICS therapy also may decrease the risk of cardiovascular disease, and perhaps of all-cause mortality. We examined this hypothesis in a large, well-characterized cohort of asthmatic women. METHODS: In 1976, the Nurses' Health Study enrolled 121,700 registered nurses, who were 30 to 55 years of age. Participants were asked about "physician-diagnosed asthma" on biennial questionnaires. In 1998, asthmatic participants were sent a supplementary questionnaire on asthma diagnosis and management, including ICS use. Mortality was assessed through 2003, without knowledge of the 1998 (baseline) ICS status. The odds ratios (ORs) for death were adjusted for age, asthma severity, smoking, heart disease, cancer, stroke, aspirin, and statin use. RESULTS: Among 2,671 eligible women (ie, those who responded to the 1998 supplement [85%], met criteria for persistent asthma, and had not received a prior diagnosis of COPD), 54% reported ICS use. Over the next 5 years, 87 women (3.3%) died (cardiovascular deaths, 22; cancer deaths, 31; other, 34 [including 4 from asthma]). Compared to asthmatic women who did not use ICSs, those receiving therapy with ICSs had lower all-cause mortality (OR, 0.58; 95% confidence interval [CI], 0.36 to 0.92). ICS users were at significantly lower risk of cardiovascular death (OR, 0.35; 95% CI, 0.13 to 0.93), but not of death from cancer (OR, 0.66; 95% CI, 0.32 to 1.38) or other causes (OR, 0.62; 95% CI, 0.30 to 1.27). CONCLUSIONS: ICS use was associated with significantly lower cardiovascular and all-cause mortality in women with asthma. These observational data suggest that ICSs may indeed have antiinflammatory benefits beyond the airway, which is a possibility that merits further study.     

Managing Asthma in Expectant Mothers

Pregnancy does not appear to have a consistent effect on the frequency or severity of asthma. The most common cause of worsening asthma in pregnancy is likely to be noncompliance with medication. Emphasizing to the patient in advance that fetal well-being is dependent on maternal well-being may help prevent this.In general, well controlled asthma is not associated with a higher risk of adverse pregnancy outcomes. Essential to successful asthma management is patient education that helps to ensure effective medication use, avoidance of triggers, and prompt treatment. This education should include measurement of peak expiratory flow rate and a written asthma action plan. Most of the medications that are used to control asthma in the general population can be safely used in pregnant women. Inhaled beta-adrenoceptor agonists (beta-agonists), cromolyn sodium (sodium cromoglycate), and inhaled and systemic corticosteroids all appear to be very well tolerated by the fetus. Budesonide and beclomethasone should be considered as the preferred inhaled corticosteroids for the treatment of asthma in pregnancy. Use of the leukotriene receptor antagonists zafirlukast and montelukast in pregnancy is probably safe but should be limited to special circumstances, where they are viewed essential for asthma control. Zileuton should not be used in pregnancy.Acute asthma exacerbations in pregnant women should be treated in a similar manner to that in non-pregnant patients. Maternal blood glucose levels should be monitored periodically in pregnant women receiving systemic corticosteroids because of the deleterious effects of hyperglycemia upon embryos and fetuses. During pregnancy, maternal arterial oxygen saturations should be kept above 95% if possible for fetal well-being. Ambulatory oxygenation should be checked prior to discharge to ensure that women do not desaturate with their daily activities.Acute exacerbations of asthma during labor and delivery are rare. Dinoprost, ergometrine, and other ergot derivatives can cause severe bronchospasm, especially when used in combination with general anesthesia, and should be avoided in asthmatic patients. Pregnant women who have been treated with corticosteroids in the past year may require stress-dose corticosteroids during labor and delivery. Most asthma medications, including oral prednisone, are considered compatible with breast-feeding.     

Recommendations for treatment of intermittent mild persistent asthma in children and adolescents

Many parents and caretakers of children and adolescents with mild persistent asthma (MPA) do not follow proposed guidelines, namely the daily and continuous administration of inhaled corticosteroids (ICS). Instead, parents and caretakers tend to use ICS and bronchodilators intermittently for short periods and restart such therapy only when symptoms reappear. It is our opinion that intermittent treatment of MPA in children and adolescents might achieve the same level of asthma control as has been achieved in adults. We propose, therefore, that after an initial period of stabilization with age‐appropriate doses of oral glucocorticoids or high‐dose ICS and short‐acting beta‐2 agonists (SABA), caretakers can stop treatment once there are no longer signs or symptoms of asthma. When asthmatic symptoms recur, treatment should be restarted with ICS and SABA, or oral corticosteroids if the exacerbation is severe. The perception of developing asthma symptoms remains an unsolved problem. Based on our clinical experience in children and adolescents with asthma, we list a number of signs and symptoms that precede an exacerbation of asthma, allowing for an early re‐introduction of treatment to prevent an exacerbation. Pediatr Pulmonol. 2009; 44:205–208. © 2009 Wiley‐Liss, Inc.     

Asthma in pregnancy.

Asthma, one of the most common serious medical problems to complicate pregnancy, affects 3-8% of pregnancies in the United States. The goals of therapy in the pregnant asthmatic patient do not differ from those in non-pregnant patients. Inhaled corticosteroids (ICS) are preferred in the management of all levels of persistent asthma in pregnant patients, because these agents have been shown to reduce asthma exacerbations during pregnancy. Asthma in pregnancy is often undertreated due to physician and patient concerns over the effects of asthma medications on the fetus. However, undertreatment leads to loss of asthma control and increases in maternal morbidity, perinatal mortality, preeclampsia, preterm birth, and low birth weight infants. Recent prospective clinical cohort studies with active asthma management by NAEPP guidelines show no evidence of increased maternal or fetal morbidity or mortality. Therefore, it is critical for the mother to understand that failure to control asthma during pregnancy may lead to poor outcomes. A case study follows to highlight clinical pearls and pitfalls in the management of asthma in the pregnant patient.     

妊娠期支气管哮喘治疗进展

临床研究已证明妊娠期重度及控制不佳的支气管哮喘(简称哮喘)与母亲及胎儿严重并发症相关.对于妊娠期哮喘患者,接受药物治疗比存在哮喘症状和哮喘发作更安全.所有程度的持续妊娠哮喘患者都应当应用吸入糖皮质激素作为控制药物,首选布地奈德.白三烯受体拮抗剂可以缓解支气管痉挛、减轻症状、改善肺功能.长效β2受体激动剂对于正在应用吸入糖皮质激素的患者可作为首选的添加药物.吸入短效β2受体激动剂可以作为缓解药物.对于正在接受维持量或接近维持量治疗,无不良反应、临床疗效好的妊娠哮喘患者可以继续进行变应原免疫治疗.     

Trends in asthma self-management skills and inhaled corticosteroid use during pregnancy and postpartum from 2004 to 2017

Objective: Asthma exacerbations and medication non-adherence are significant clinical problems during pregnancy. While asthma self-management education is effective, the number of education sessions required to maximise asthma management knowledge and inhaler technique and whether improvements persist postpartum, are unknown. This paper describes how asthma knowledge, skills, and inhaled corticosteroid (ICS) use have changed over time. Methods: Data were obtained from 3 cohorts of pregnant women with asthma recruited in Newcastle, Australia between 2004 and 2017 (N = 895). Medication use, adherence, knowledge, and inhaler technique were compared between cohorts. Changes in self-management knowledge/skills and women's perception of medication risk to the fetus were assessed in 685 women with 5 assessments during pregnancy, and 95 women who had a postpartum assessment. Results: At study entry, 41%, 29%, and 38% of participants used ICS in the 2004, 2007, and 2013 cohorts, respectively (p = 0.017), with 40% non-adherence in each cohort. Self-management skills of pregnant women with asthma did not improve between 2004 and 2017 and possession of a written action plan remained low. Maximum improvements were reached by 3 sessions for medications knowledge and one session for inhaler technique, and were maintained postpartum. ICS adherence was maximally improved after one session, but not maintained postpartum. Perceived risk of asthma medications on the fetus was highest for corticosteroid-containing medication; and was significantly reduced following education. Conclusions: There was a high prevalence of non-adherence and poor self-management skills in all cohorts. More awareness of the importance of optimal asthma management during pregnancy is warranted, since no improvements were observed over the past decade.     

Pharmacologic interventions to reduce the risk of asthma exacerbations

Inhaled corticosteroids (ICS) are known to reduce the risk of asthma exacerbations and asthma fatalities. In addition, an increased dose of ICS at the onset of exacerbation can reduce the need for systemic corticosteroids, although this may require a fourfold increase in dose. The overuse of short-acting beta(2)-agonists or long-acting inhaled beta(2)-agonists, used as monotherapy, increases these risks. By contrast, the use of long-acting beta(2)-agonists together with ICS has been demonstrated to reduce the doses of ICS needed for ideal asthma control, as well as to reduce asthma exacerbations. This has been best demonstrated in the Formoterol and Corticosteroids Establishing Therapy and Oxis and Pulmicort Turbuhaler in the Management of Asthma studies, which demonstrated that the combination of inhaled budesonide and formoterol reduced the risk of asthma exacerbations over that achieved by budesonide alone. Even the "as needed" use of inhaled formoterol added to ICS reduces asthma exacerbations. The combination inhaler, Symbicort, containing both budesonide and formoterol, reduced the risk of asthma exacerbations to a similar extent as the monocomponents, given separately. Treatment with either leukotriene receptor antagonists or anti-IgE also reduces the risks of asthma exacerbations, but the magnitude of the benefit compared with the combination of ICS and long-acting beta(2)-agonists is not yet known.     

Global Initiative for Asthma Strategy 2021. Executive Summary and Rationale for Key Changes

The Global Initiative for Asthma (GINA) Strategy Report provides clinicians with an annually updated evidence-based strategy for asthma management and prevention, which can be adapted for local circumstances (e.g., medication availability). This article summarizes key recommendations from GINA 2021, and the evidence underpinning recent changes.GINA recommends that asthma in adults and adolescents should not be treated solely with short-acting β₂-agonist (SABA), because of the risks of SABA-only treatment and SABA overuse, and evidence for benefit of inhaled corticosteroids (ICS). Large trials show that as-needed combination ICS–formoterol reduces severe exacerbations by ≥60% in mild asthma compared with SABA alone, with similar exacerbation, symptom, lung function, and inflammatory outcomes as daily ICS plus as-needed SABA.Key changes in GINA 2021 include division of the treatment figure for adults and adolescents into two tracks. Track 1 (preferred) has low-dose ICS–formoterol as the reliever at all steps: as needed only in Steps 1–2 (mild asthma), and with daily maintenance ICS–formoterol (maintenance-and-reliever therapy, “MART”) in Steps 3–5. Track 2 (alternative) has as-needed SABA across all steps, plus regular ICS (Step 2) or ICS–long-acting β₂-agonist (Steps 3–5). For adults with moderate-to-severe asthma, GINA makes additional recommendations in Step 5 for add-on long-acting muscarinic antagonists and azithromycin, with add-on biologic therapies for severe asthma. For children 6–11 years, new treatment options are added at Steps 3–4.Across all age groups and levels of severity, regular personalized assessment, treatment of modifiable risk factors, self-management education, skills training, appropriate medication adjustment, and review remain essential to optimize asthma outcomes.     

Real-world evaluation of asthma reliever therapy among continuous users of asthma maintenance medication in Japan: A retrospective cohort study using a claims database

BackgroundThe decrease in mortality rate owing to asthma has slowed in recent years. A large proportion of patients with asthma remain uncontrolled in Japan. This study aimed to determine the prevalence of short-acting beta 2 agonists (SABA) overuse and its associated factors.MethodsThis large-scale retrospective cohort study analyzed continuously treated patients with asthma aged 15–74 years between January 2017 and December 2017 using a Japanese insurance claims database. Characteristics, disease information, and prescribed drugs were extracted from the database, and treatment steps were defined according to drug combinations based on the criteria of the Japanese asthma guidelines. SABA overuse was defined as ≥3 canisters per year. Factors associated with SABA overuse were estimated using multivariable logistic regression.ResultsAmong 7,483 patients with mild-to-moderate asthma, 7,001 (93.6%) and 482 (6.4%) had low and high SABA use, respectively. Inhaled corticosteroids (ICS)/long-acting β-agonists (LABA) were the main asthma control treatments. The proportions of patients who overused SABA were 347 (9.9%) and 1,201 (5.6%) in the ICS and ICS/LABA groups, respectively. The factors associated with SABA overuse were male sex, ICS monotherapy, higher treatment steps, no history of allergic rhinitis, no history of chronic sinusitis, and no asthma management.ConclusionsThere is a relatively low prevalence of SABA overuse among asthmatic patients in Japan. ICS/LABA therapy, treatment steps, allergic rhinitis, chronic sinusitis, and asthma management are associated with a decreased risk of SABA overuse. Further studies are needed to investigate the association between SABA overuse and asthma exacerbation and mortality.     

Inhaled Glucocorticosteroid and Long-Acting β<Subscript>2</Subscript>-Adrenoceptor Agonist Single-Inhaler Combination for Both Maintenance and Rescue Therapy

Despite aggressive fixed-dose (FD) combination therapy with inhaled glucocorticosteroids (ICS) and long acting beta(2)-adrenoceptor agonists (LABA), many patients with asthma remain suboptimally controlled, based on the need for rescue therapy and rates of severe exacerbations. The strategy of adjustable maintenance dosing (AMD) involves adjustment of the maintenance dose, (using a single combination [budesonide/formoterol] inhaler, Symbicort((R))) in response to variability of asthma control over time. The AMD strategy, like the FD approach, involves the use of a short-acting beta(2)-adrenoceptor agonist (SABA) for rapid relief of bronchospasm. The dose-response characteristics of budesonide/formoterol make the AMD strategy a feasible option that cannot be exploited with the combination of salmeterol/fluticasone propionate (Advair((R))). Several studies suggest that the AMD strategy is superior to a FD approach in terms of overall asthma control.Budesonide/formoterol in a single inhaler is as effective as albuterol (salbutamol) for relief of acute asthma episodes, a feature that makes it possible to use this combination for both maintenance and reliever therapy without the need for the use of a SABA. The single-inhaler strategy has been shown to be safe and more efficacious than FD therapy. In particular, the COSMOS study has demonstrated that exacerbation burden is reduced more effectively when the combination (budesonide/formoterol) single inhaler is used for both maintenance and relief compared with FD therapy with salmeterol/fluticasone and albuterol for rescue in patients with moderate-to-severe asthma. These findings suggest that we will have to reconsider our definition of reliever therapy for patients that require long-term therapy with combination ICS and LABA.The concept of single-inhaler therapy represents a paradigm shift in asthma management that has been validated in several large studies involving thousands of patients. The single-inhaler strategy represents one of the most significant advances in asthma management in many years, and one that appears ideal for adoption in primary care.     

International trends in admissions and drug sales for asthma.

OBJECTIVE: To test whether national patterns of asthma drug use, particularly inhaled corticosteroids (ICS), are related to the rate of acute severe asthma exacerbations. DESIGN: The relation of international trends in hospital admissions for asthma with asthma drug sales was examined using country-specific regressions over the period 1990-1999. Pooled estimates of the regression coefficients were calculated using random effects models. RESULTS: Data on asthma admissions and asthma drug sales (including the sub-category ICS) were obtained from 11 countries. There was a negative relationship between falling admissions and rising sales of respiratory drugs and ICS in 9 of these 11 countries. A pooled estimate of the change in asthma admission rate per 10,000 associated with a unit increase in sales rate was -6.3 (95% CI -10.4 - -2.3) for all asthma drugs and -11.2 (95% CI -19.7 - -2.8) for ICS. CONCLUSION: At the national level, there is good evidence that over the last decade, increased sales of asthma drugs, and ICS in particular, were associated with a decline in rates of hospital admission for asthma. This is consistent with a beneficial effect of increasing use of asthma drugs, but other explanations such as decreasing prevalence could also be responsible.     

Association of Exhaled Nitric Oxide to Asthma Burden in Asthmatics on Inhaled Corticosteroids

Background. Fractional exhaled nitric oxide (FENO) is a marker of airway inflammation. Its role in assessing asthma burden in clinical practice needs more study. Objective. To determine whether higher FENO levels are associated with greater asthma burden. Methods. This was a multicenter cross-sectional retrospective study of atopic 12- to 56-year-old persistent asthmatics on inhaled corticosteroids (ICS). Questionnaire and 1-year retrospective administrative data were used to analyze by unadjusted and adjusted robust Poisson regression (relative risks) and negative binomial regression [incidence rate ratios (IRRs)] the associations of masked FENO levels (NIOX MINO®) to short-acting beta-agonist (SABA) dispensings and oral corticosteroid (OCS) use in the past year independent of spirometry and an asthma control tool [Asthma Control Test (ACT)]. Results. FENO levels ranged from 7–215ppb (median 28ppb) in 325 patients. Higher FENO levels significantly correlated with more SABA dispensings and OCS courses in the past year, lower FEV₁% predicted levels, but not ACT score. FENO highest (≥48ppb) versus lowest (≤19ppb) quartile values were associated independently in the past year with ≥7 SABA canisters dispensed (relative risk=2.40, 95% CI=1.25–4.62) and total number of SABA canisters dispensed (IRR=1.46, 95% CI=1.12–1.99) and with ≥1 OCS course (relative risk=1.48, 95% CI=1.06-2.07) and total number of OCS courses (IRR=1.71, 95% CI=1.09–2.66). The significant independent relationship of higher FENO levels to increasing SABA dispensings and OCS courses was confirmed by linear trend analyses. Conclusions. Independent and clinically meaningful associations between higher FENO levels and greater asthma burden during a prior year in persistent asthmatics on ICS suggest that FENO measurement may be a complementary tool to help clinicians assess asthma burden.     

What have we learnt about asthma control from trials of budesonide/formoterol as maintenance and reliever?

Despite improvements in medications, devices and understanding of the disease, about half of all asthma patients worldwide remain inadequately controlled, suggesting the need for a new approach to asthma management. Poor adherence to prescribed maintenance therapy and over‐reliance on SABA reliever medication is a common cause of inadequate control. This article reviews published data from 6‐ to 12‐month, double‐blind, RCT and open‐label real‐world studies involving budesonide/formoterol maintenance and reliever therapy (MART) and relevant comparator approaches to asthma management, and considers how these compare in achieving the treatment goals described in guidelines. The data confirm that patients with asthma treated with budesonide/formoterol MART achieved the same or better asthma symptom control compared with ICS/LABA plus SABA regimens at similar or higher ICS doses, with consistently lower rates of exacerbations and considerably lower annual requirement for oral corticosteroids. These findings have been confirmed across a range of severities of persistent asthma. With the MART approach, maintenance dosing ensures coverage for day‐to‐day control, and the use of a reliever with anti‐inflammatory properties (budesonide/formoterol) provides extra doses of ICS as soon as symptoms prompt the use of reliever, resulting in a 40–50% reduction of exacerbations compared with an ICS‐based treatment approach plus as‐needed SABA as reliever. As‐needed, budesonide/formoterol has also recently been shown to be more effective as a reliever in mild asthma than SABA alone, reducing exacerbations by up to 64% in the SYGMA studies.     

Asthma exacerbations: pharmacological prevention

Asthma exacerbations are responsible for many emergency medical interventions and account for a significant proportion of the health costs of the disease. Increased airway inflammation is a key feature of exacerbations in asthma and therefore inhaled corticosteroids (ICS) are considered as first-line therapy for long-term asthma control. ICS have been demonstrated to reduce the risk of asthma exacerbations, as well as improving lung function. Oral leukotriene receptor antagonists also reduce the incidence of asthma exacerbations but are less effective than ICS. In patients with inadequately controlled persistent asthma despite low-dose ICS, the addition of a long-acting inhaled beta-agonist (LABA) should be considered. LABA should not be given alone and should always be associated with ICS in asthma. The anti-immunoglobulin E antibody, omalizumab, reduces severe exacerbations and emergency visits in patients with severe allergic asthma. In clinical trials measurement of the inflammatory response in induced sputum could provide information concerning appropriate drug therapy. Asthma-associated comorbidities should be investigated and treated, particularly in severe asthma. Despite a high prevalence of both gastro-oesophageal reflux and allergic rhinitis among patients with asthma, treatment with proton-pump inhibitors or nasal corticosteroids does not reduce the rate of asthma exacerbations.     

Asthme et grossesse

Any asthmatic woman in the childbearing age may become pregnant. Generally, asthma is not a contraindication for pregnancy, and drug treatment of pregnant asthmatic women is indicated. Neither mother nor child are particularly at risk for complications, as demonstrated in recently published long-term studies. Pharmacologic data are reassuring, especially those concerning inhaled corticosteroids. Nevertheless, regular follow-up of asthmatic pregnant patients is necessary to assure good control of the patient's asthma.     

Budesonide/formoterol for maintenance and relief in uncontrolled asthma vs. high-dose salmeterol/fluticasone

BACKGROUND: Budesonide/formoterol maintenance and reliever therapy (Symbicort SMART) improves asthma control compared with fixed-dose inhaled corticosteroid/long-acting beta(2)-agonist (ICS/LABA) regimens, but its efficacy has not been assessed in comparison with sustained high-dose salmeterol/fluticasone (Seretide) plus a short-acting beta(2)-agonist (SABA). METHODS: Patients (N=2309) with symptomatic asthma (aged 12 years; forced expiratory volume in 1s 50% predicted), who had experienced an asthma exacerbation in the previous year, were randomised to receive budesonide/formoterol 160/4.5 microg two inhalations twice daily and as needed, or one inhalation of salmeterol/fluticasone 50/500 microg twice daily plus terbutaline as needed, for 6 months. RESULTS: Time to first severe exacerbation, the pre-specified primary outcome, was not significantly prolonged (risk ratio 0.82; 95% confidence interval 0.63, 1.05). Budesonide/formoterol maintenance and reliever therapy reduced total exacerbations from 31 to 25 events/100 patients/year (P=0.039), and exacerbations requiring hospitalisation/emergency room (ER) treatment from 13 to 9 events/100 patients/year (P=0.046). The treatments showed no difference in measures of lung function or asthma symptoms. The mean dose of ICS received was lower using budesonide/formoterol maintenance and reliever therapy (792 microg/day budesonide [1238 microg/day beclomethasone dipropionate (BDP) equivalent] versus 1000 microg/day fluticasone [2000 microg/day BDP equivalent] with salmeterol/fluticasone therapy; P<0.0001). Both treatments were well tolerated. CONCLUSION: In the treatment of uncontrolled asthma, budesonide/formoterol maintenance and reliever therapy reduces the incidence of severe asthma exacerbations and hospitalisation/ER treatment with similar daily symptom control compared with sustained high-dose salmeterol/fluticasone plus SABA. This benefit is achieved with substantially less ICS exposure.     

Effectiveness of drug treatment strategies to prevent asthma exacerbations and increase symptom-free days in asthmatic children: a network meta-analysis

Objective: To determine the effectiveness and safety of current maintenance therapies that include inhaled corticosteroids (ICS), long-acting β-agonists (LABA) and/or leukotriene receptor antagonists (LTRAs) in preventing exacerbations and improving symptoms in pediatric asthma. Methods: A systematic review with network meta-analysis was conducted after a comprehensive search for relevant studies in the PubMed, Cochrane Library, Embase and Clinical Trials databases, up to July 2014. Randomized clinical trials were selected comparing treatment strategies of the Global Initiative for Asthma guidelines. The full-text randomized clinical trials compared maintenance treatments for asthma in children (≤18 years) of ≥4 weeks duration, reporting exacerbations or symptom-free days. The primary and secondary effectiveness outcomes were the rates of moderate/severe exacerbations and symptom-free days from baseline, respectively. Withdrawal rates were taken as the safety outcome. Results: Included in the network meta-analysis was 35 trials, comprising 12?010 patients. For both primary and secondary outcomes, combined ICS and LABA was ranked first in effectiveness (OR 0.70, 95% CI: 0.52–0.97 and OR 1.23, 95% CI: 0.94–1.61, respectively, compared with low-dose ICS), but the result of secondary outcomes was statistically insignificant. Low-dose ICS, medium- or high-dose ICS and combined ICS and LTRA strategies were comparable in effectiveness. ICS monotherapies, and ICS?+?LABA and ICS?+?LTRA strategies were similarly safe. High-dose ICS had the highest rate of total withdrawals, but the difference was not significant. Conclusions: Combined ICS and LABA treatments were most effective in preventing exacerbations among pediatric asthma patients. Medium- or high-dose ICS, combined ICS and LTRAs, and low-dose ICS treatments seem to be equally effective.