Safety Of Long-acting Beta-agonists Research Articles

Long-Acting β2-Agonists and Risk of Hypertensive Disorders of Pregnancy: A Cohort Study

Maternal asthma has been found to be associated with an increased risk of hypertensive disorders of pregnancy (HDP), that is, gestational hypertension, preeclampsia, and eclampsia. There is limited data, however, regarding the relationship between the use of long-acting beta-agonists (LABAs) during pregnancy and these outcomes. To investigate whether exposure to a LABA in addition to an inhaled corticosteroid increases the risk of HDP or preeclampsia/eclampsia, as compared with nonexposure to LABAs, in pregnant women with asthma. A cohort of 8,936 pregnancies in women with asthma who delivered between 1998 and 2010 was reconstructed using Quebec (Canada) health administrative databases. Cox proportional hazard regression models, adjusted for potential confounders, were used for statistical analyses. The primary exposure was LABA use (yes/no) measured on the first day of the 20th week of pregnancy. HDP were identified on the basis of recorded diagnoses and on prescriptions of antihypertensive drugs filled on or after the first day of week 20 of gestation. There were 567 (6.3%) cases of HDP and 256 (2.9%) cases of preeclampsia/eclampsia in the cohort, and the rates of both disorders were similar in women exposed or not exposed to LABAs. LABA use was not associated with increased risks of HDP (adjusted hazard ratio, 0.96; 95% CI, 0.69-1.33) or preeclampsia/eclampsia (adjusted hazard ratio, 0.89; 95% CI, 0.53-1.50). The results of this study provide evidence suggesting the safety of LABAs for the treatment of asthma in pregnancy, in terms of the risks of HDP and preeclampsia/eclampsia.

Combination corticosteroid/β-agonist inhaler as reliever therapy: A solution for intermittent and mild asthma?

The recommended treatment of mild asthma is regular maintenance inhaled corticosteroids (ICSs) with a short-acting β-agonist as a separate inhaler used when needed for symptom relief. However, the benefits of regular ICS use in actual clinical practice are limited by poor adherence and low prescription rates. An alternative strategy would be the symptom-driven (as-required or "prn") use of a combination ICS/short-acting β-agonist or ICS/long-acting β-agonist inhaler as a reliever rather than regular maintenance use. The rationale for this approach is to titrate both the ICS and β-agonist dose according to need and enhance ICS use in otherwise poorly adherent patients who overrely on their reliever β-agonist inhaler. This strategy will only work if the β-agonist component has a rapid onset of action for symptom relief. There is evidence to suggest that this regimen has advantages over regular ICS therapy and might represent an effective, safe, and novel therapy for the treatment of intermittent and mild asthma. In this commentary we review this evidence and propose that randomized controlled trials investigating different combination ICS/β-agonist inhaler products prescribed according to this regimen in intermittent and mild asthma are an important priority.

Safety of long-acting beta agonists and inhaled corticosteroids in children and adolescents with asthma.

The introduction of long-acting beta agonists (LABAs) was considered a major advance in bronchodilator therapy for adult, as well as pediatric, patients with asthma. However, the use of LABAs has raised safety concerns, especially the potential for severe asthma exacerbations (SAEs) resulting in hospitalizations or even death. Meanwhile, the use of inhaled corticosteroids (ICSs), a cornerstone in the treatment of mild-to-severe persistent asthma, has been associated with growth suppression in children. The purpose of this review was to identify and discuss the major published safety studies surrounding LABA, ICS, and combined LABA/ICS usage in children. By way of a critical search for influential published clinical trials, meta-analyses, and observational studies, six studies relevant to the safety of LABA monotherapy, seven studies relevant to ICS monotherapy, and four studies on the subject of LABA/ICS combination usage were identified and reviewed. Based on the reviewed literature, the controversy surrounding these anti-asthma medications was clearly exposed. On the one hand, there is some evidence that LABA monotherapy may be associated with SAEs and asthma-related death, while ICS monotherapy may be associated with a higher risk of growth suppression. On the other hand, the concurrent use of a LABA with an ICS has been associated with positive outcomes including symptom reduction and reduced rate and severity of exacerbations. Further clinical research is warranted and has been called for by the US Food and Drug Administration.

The FDA-mandated trial of safety of long-acting beta-agonists in asthma: finality or futility?

In 2010, in response to a prolonged debate over the safety of long-acting beta-agonists (LABAs), the United States Food and Drugs Administration (FDA) issued guidelines for the use of LABAs...

Adjusting Controller Medications in Children: Evidence for Step Up and Down Choices after EPR-3

Evidence regarding long-acting beta-agonist safety and specific step up and step down recommendations in children that have been published since the National Asthma Education Prevention Program Guidelines for the Diagnosis and Management Expert Panel Report 3 are reviewed. Despite several systematic reviews involving many thousands of patients, the safety of long-acting beta-agonists in children remains under debate. Although the role of inhaled corticosteroids has been well established in children, whether the ideal add on therapy should be a long-acting betaagonist or a leukotriene receptor antagonist, balancing efficacy with safety information, remains controversial. The ideal step down regimen to be used after asthma control has been achieved is similarly not well established. Additional research in children is needed to answer these questions, particularly in the youngest age groups. Keywords: Asthma, guidelines, leukotriene receptor antagonists, long-acting beta-agonists, pediatric, pharmacotherapy

Risk of serious asthma exacerbations associated with long-acting beta agonists among patients with asthma: A retrospective cohort study

After the Serevent Nationwide Surveillance clinical trial, controversy has surrounded the safety of long-acting beta agonists (LABAs). Examine the association between LABAs and severe asthma exacerbations (SAEs). From a multistate Medicaid database, for the years 2002-2007, a total of 940,449 patients (age <40) with asthma were selected and divided into a cohort with newly-diagnosed asthma and one with pre-existing asthma. SAEs included asthma-related emergency department (ED) visits, hospitalizations, and intubations. Patients' asthma severity was determined based on medication regimen as suggested by the 2002 National Asthma Guidelines. Specific use of inhaled corticosteroids (ICSs), LABAs, ICS/LABA combination drugs, short-acting beta agonists (SABAs), and other drugs was tracked. Cox proportional hazard regressions were estimated to assess the risk of SAEs associated with patient severity, drug use, and covariates. Compared to patients taking a SABA only, estimated SAE hazard ratios for newly diagnosed and pre-existing-asthma patients were as follows: 0.63 (95% CI 0.58-0.69) and 0.74 (0.70-0.79) for patients on a LABA without ICS, and 0.79 (0.77-0.81) and 0.90 (0.87-0.92) for those on a LABA/ICS single inhaler. Although hazard ratios were estimated to be similar for ED visits, LABA use was found to be positively associated with hospitalizations and intubations. Other key risk factors (P < .0001) included being African American, an alcohol/substance use disorder, pregnancy, and obesity. Relative to SABA-only therapy, LABA use is associated with a lower risk of ED visit. Certain patients with asthma, such as pregnant women and African Americans, are particularly vulnerable to SAE risk of all types.

Evaluating Safety of Long-Acting Beta Agonists (LABAs) in Patients with Asthma

The introduction of long-acting beta agonists (LABAs) was considered a major advance in bronchodilator therapy with evidence that their use led to improved lung function and quality of life. However, the use of LABAs has raised safety concerns, such as their potential to provoke severe asthma exacerbations (SAEs) and death. This systematic review of major findings discusses the safety controversy surrounding LABA therapy and provides background for the U.S. Food and Drug Administration's warnings concerning LABA use. Findings from large clinical trials and several meta-analyses are described and compared in terms of their implications for the safety of LABAs. Monotherapy LABA therapy in the treatment of asthma remains controversial and is not recommended by the most recent asthma management guidelines. Despite the existence of numerous published studies, we conclude that more well-designed research on this topic --- to determine whether LABAs are associated with SAEs, such as asthma-related hospitalizations, intubations, and emergency room visits, or death --- is required. Particularly needed is research that makes use of large, secondary longitudinal databases.

Risks of Long-Acting Beta-Agonists in Achieving Asthma Control

In early December 2008, the Food and Drug Administration (FDA) held an unusual joint meeting of the Pulmonary–Allergy Drugs Advisory Committee, the Drug Safety and Risk Management Advisory Committee, and the Pediatric Advisory Committee to consider the safety of long-acting beta-agonists (LABAs). The meeting is described in detail in a Perspective in this issue of the Journal by Kramer,1 who points out that decision making by the advisers and the FDA was hampered by the lack of data about the safety of LABAs. LABAs, which are administered by inhalation, act by effecting prolonged stimulation of the β2-adrenergic receptor. . . .

Review: Long-acting β-agonists do not increase risk for asthma-related hospitalization in patients taking inhaled corticosteroids

Source Citation Jaeschke R, O’Byrne PM, Mejza F, et al. The safety of long-acting beta-agonists among patients with asthma using inhaled corticosteroids: systematic review and metaanalysis. Am J Respir Crit Care Med. 2008;178:1009-16. 18776152

Is it safe to use long‑acting β‑agonists in asthma and chronic obstructive pulmonary disease? Implications of recent trials and meta‑analyses

The safety of long-acting beta-agonists (LABAs) has been hotly debated for several years, with surveillance studies suggesting increased risk of mortality, especially with use of LABA without inhaled corticosteroid (ICS). Meta-analyses of selected trials, especially those dominated by one large study, report significantly increased risks for mortality and Serious Adverse Events (SAEs). Review of all of the available evidence from clinical trials, and meta-analyses using different selection criteria, suggests that LABA with ICS in fact significantly reduces SAEs. The risk of mortality is more difficult to assess, but post-hoc analyses suggest the risk is increased with LABA monotherapy and not with concomitant use of ICS. In both asthma and chronic obstructive pulmonary disease, concomitant use of ICS should be considered best practice whenever LABAs are used.

Safety of regular use of long-acting beta agonists as monotherapy or added to inhaled corticosteroids in asthma. A systematic review

Background Safety of long-acting beta agonists (LABA) has been questioned and recent evidence suggested a detrimental effect on asthma control as well as an increased risk of death. Objective To evaluate the safety of regular use of LABA compared with placebo or LABA added to inhaled corticosteroids (ICS) compared with ICS in persistent asthma. Methods Randomized studies from MEDLINE, EMBASE, and Cochrane Controlled Trials Register were identified. Additionally, AstraZeneca, GlaxoSmithKline, Novartis and FDA clinical trials databases were searched. Primary outcomes were asthma exacerbations (AE) requiring systemic corticosteroids or hospitalization, life-threatening exacerbations and asthma-related deaths. Results We identified 92 randomized clinical trials with 74,092 subjects. LABA (as monotherapy) reduced exacerbations requiring corticosteroids (Relative Risk [RR] = 0.80; 95% CI, 0.73–0.88), without detrimental effects on hospitalizations or life-threatening episodes. Contrarily, LABA showed a significant increase in asthma-related deaths (Relative Risk = 3.83; 95% CI, 1.21–12.14). Subgroup analysis suggests that children, patients receiving salmeterol, and a duration of treatment >12 weeks are associated with a higher risk of serious adverse effects; also there was a protective effect of concomitant use of ICS. On the other hand, combination of LABA/ICS reduced exacerbations (RR = 0.73; 95% CI, 0.67–0.79), and hospitalizations (RR = 0.58, 95% CI, 0.45–0.74). Combined therapy was also equivalent to ICS in terms of life-threatening episodes and asthma-related deaths. Again, children and use of salmeterol were associated with an increased risk of some severe outcomes as compared with adults and formoterol users, respectively. Conclusions This review reinforced the international recommendations in terms of the use of LABA remains the preferred add-on therapy to ICS for patients whose disease cannot adequately controlled with ICS, and that LABA cannot be prescribed as a monotherapy. Nevertheless, in spite of the protective effect of the ICS, children and salmeterol use still show an increased risk of non-fatal serious adverse events.

Safety of Long-Acting Beta-Agonists

Safety of Long-Acting Beta-Agonists

Understanding the pathophysiology of severe asthma to generate new therapeutic opportunities

Although asthma is defined in terms of reversibility of airflow obstruction, as the disease becomes more severe and chronic, it adopts different characteristics, including a degree of fixed airflow obstruction and corticosteroid refractoriness. Underlying these phenotypes is evidence of airway wall remodeling, which should be distinguished from the increase in smooth muscle linked to airways hyperresponsiveness. Aberrant epithelial-mesenchymal communication leads to a chronic wound scenario, which is characterized by activation of the epithelial-mesenchymal trophic unit, epithelial damage, the laying down of new matrix, and greater involvement of neutrophils in the inflammatory response. In allergic asthmatic patients who remain symptomatic despite high-dose corticosteroid therapy, blockade of IgE with omalizumab confers appreciable clinical benefit. Chronic severe asthma is also accompanied by a marked increase in TNF-alpha production that might contribute to corticosteroid refractoriness. Based on this, TNF blockade with the soluble fusion protein entanercept produces improvement in asthma symptoms, lung function, and quality of life paralleled by a marked reduction in airways hyperresponsiveness. Identification of novel susceptibility genes, such as a disintegrin and metalloprotease 33 (ADAM33), will provide further targets against which to direct novel therapies for asthma, especially at the more severe end of the disease spectrum.

Safety of Long-Acting Beta-Agonists — An Urgent Need to Clear the Air

Eleven years after the first long-acting beta-agonist, salmeterol, was approved for sale in the United States, the Food and Drug Administration (FDA) has issued a stern public health advisory alerting “health care professionals and patients that these medicines may increase the chance of severe asthma episodes, and death when those episodes occur” (www.fda.gov/cder/drug/advisory/LABA.htm). The announcement followed a July 2005 meeting of an FDA advisory committee on this topic. What are the consequences of this advisory for the treatment of asthma?Currently, inhaled corticosteroids are the most effective treatment for the symptoms of persistent asthma. However, in patients with severe disease, . . .