The Salmeterol Multicenter Asthma Research Trial: A Comparison of Usual Pharmacotherapy for Asthma or Usual Pharmacotherapy Plus Salmeterol; H.S. Nelson, S.T. Weiss, E.R. Bleecker, S.W. Yancey, P.M. Dorinsky, SMART Study Group (Chest 2006 Jan; 129(1):15–26).
Study Objective.
To compare the safety of Salmeterol xinafoate or placebo added to usual asthma care. Design: A 28-week, randomized, double-blind, placebo-controlled, observational study. Setting. Study subjects were seen once in the study physician's office for screening and were provided all blinded study medication for the entire study period. Follow-up by telephone was scheduled every 4 weeks. Participants. Subjects (> 12 years old) with asthma as judged by the study physician were eligible. Individuals with a history of long-acting beta2-agonist use were excluded. Interventions. Salmeterol, 42 mug bid via metered-dose inhaler (MDI), and placebo bid via MDI. Measurements and Results. Following an interim analysis in 26,355 subjects, the study was terminated due to findings in African Americans and difficulties in enrollment. The occurrence of the primary outcome, respiratory-related deaths, or life-threatening experiences was low and not significantly different for Salmeterol vs placebo (50 vs 36; relative risk [RR] = 1.40; 95% confidence interval [CI], 0.91 to 2.14). There was a small, significant increase in respiratory-related deaths (24 vs 11; RR, 2.16; 95% CI, 1.06 to 4.41) and asthma-related deaths (13 vs 3; RR, 4.37; 95% CI, 1.25 to 15.34), and in combined asthma-related deaths or life-threatening experiences (37 vs 22; RR, 1.71; 95% CI, 1.01 to 2.89) in subjects receiving Salmeterol vs placebo. The imbalance occurred largely in the African-American subpopulation: respiratory-related deaths or life-threatening experiences (20 vs 5; RR, 4.10; 95% CI, 1.54 to 10.90) and combined asthma-related deaths or life-threatening experiences (19 vs 4; RR, 4.92; 95% CI, 1.68 to 14.45) in subjects receiving Salmeterol vs placebo. Conclusions. For the primary end point in the total population, there were no significant differences between treatments. There were small, but statistically significant increases in respiratory-related and asthma-related deaths and combined asthma-related deaths or life-threatening experiences in the total population receiving Salmeterol. Subgroup analyses suggest the risk may be greater in African Americans compared with Caucasian subjects. Whether this risk is due to factors including but not limited to a physiologic treatment effect, genetic factors, or patient behaviors leading to poor outcomes remains unknown.
Comments: This study by Nelson and colleagues spurred much controversy long before its much anticipated publication. It has lead to the “Black Box” warning by the FDA. There has been a long-standing concern about the safety and efficacy of short-acting beta agonists starting as far back as the 1960s. In this same issue Chest 2006 Jan;129(1):3–5 Paul O'Byrne and Elinor Adelroth provide an eloquent and informative editorial that reviews the history of the controversy over the safety of beta-agonists for asthma and outlines the many shortcomings of the “SMART” study design. This study recruited subjects deemed to have asthma per investigator judgement and the only objective assessment of airway function was a Peak Flow assessment at baseline. The study excluded patients who had previous use of long-acting beta agonists. Patients had no further face-to-face clinical assessment by investigators and were followed by telephone every 4 weeks but sought medical care for their asthma with their usual providers for the 28-week duration of the study. Excluding patients who had not been on long-acting beta agonists before study entry imbeds a significant bias in patient selection. These subjects were very poorly controlled asthmatics (> 60% had nocturnal symptoms, > 25% had been to an emergency department in previous months, and < 50% were being treated with inhaled corticosteroids). One must ask how such poorly controlled asthmatics could not have been on long-acting beta agonists before study entry: underestimation of their asthma severity, poor quality of medical care, poor access to care, low socioeconomic status, inability to afford medication, non-compliance. Any or all of these factors likely apply to the majority of patients who were entered into this study; however, such demographic data were not assessed. There were 6 presumed asthma-related deaths in Caucasians (71% of study population) treated with Salmeterol and 7 deaths in African Americans (18% of study population). The disproportionate number of deaths found in the male African American population may be explained by socioeconomic factors without need to invoke possible genetic polymorphisms. Table 5 shows that the majority of the 16 asthma-related deaths were in subjects on no or minimal inhaled steroids, some were on oral steroids, many were on theophylline and the cause of death included COPD in 2 patients, cardiovascular disease in 4 of the 16, and no cause of death was listed for 3 of the 16. Interestingly the subjects treated with Salmeterol were less likely to withdraw from the study due to worsening asthma. Salmeterol controls symptoms but does not control the underlying disease process and must be used with an inhaled corticosteroid and/or other anti-inflammatory agents in the treatment of asthma. Clearly this study has left many physicians concerned about the safety of using Salmeterol in COPD patients but the design flaws and the differences in the disease states render these results likely not applicable to COPD patients. There have been several studies (see next) that have not shown an increase in adverse events (including death) related to the use of Salmeterol in COPD patients.
Addition of Salmeterol to Existing Treatment in Patients with COPD: A 12-Month Study; R.A. Stockley, N. Chopra, L. Rice (Thorax 2006 Feb; 61(2):122–128).
Background.
This study investigated the addition of Salmeterol to existing treatment for exacerbations in patients with poorly reversible chronic obstructive pulmonary disease (COPD). Methods. 634 patients aged > 40 years with a history of COPD exacerbations (including at least two in the previous year) and poor reversibility of airflow obstruction (≤10% predicted forced expiratory volume in 1 second) received either Salmeterol 50 mug or placebo twice daily from a Diskus inhaler for 12 months. The primary outcome was the number of moderate and severe exacerbations. Results: The median rate of moderate or severe exacerbations in the intent-to-treat (ITT) population was lower in the Salmeterol group (0.00, range 0.0–9.8, n = 316) than in the placebo group (0.93, range 0.0–13.0, n = 318), but the difference was not statistically significant (p = 0.27). The median rate of exacerbations in the per protocol population (> 90% compliance) was also found to be lower in the Salmeterol group (0.00, range 0.0–5.0, n = 206) than in the placebo group (0.93, range 0.0–5.6, n = 195) and did reach statistical significance (p = 0.007). For secondary end points, patients receiving Salmeterol had significant improvement in lung hyperinflation measured by inspiratory capacity, which was evident at 4 weeks and maintained over 12 months (p = 0.035), and a significant improvement in health status measured by the St George's Respiratory Questionnaire at 12 months (p = 0.002). Conclusion. Salmeterol has a positive effect on symptoms and health status of patients with COPD when added to usual treatment. Exacerbations are only reduced in patients who comply with treatment.
Comments.
Given the publication of the SMART trial Stockley and colleagues' paper is timely in its study of the efficacy of Salmeterol in COPD patients. This is a well-designed study particularly in terms of the ITT and per protocol tracking of patients. The Mean FEV1 was approximately 45% in each group and they had less than 3.5% reversibility to Salbutamol (Albuterol). Approximately 22% of patients were on LABAs before starting trial. Over 50% of subjects in both groups were on inhaled corticosteroids, over 50% were on anticholinergics and over 40% were on Xanthines. This study suggests that Salmeterol is beneficial in COPD patients and that there are no significant differences in adverse events in including deaths (2%) in both groups.
Variability of Bronchial Inflammation in Chronic Obstructive Pulmonary Disease: Implications for Study Design; E. Gamble, Y. Qiu, D. Wang, J. Zhu, A. M. Vignola Dagger, C. Kroegel, F. Morell, T.T. Hansel, I.D. Pavord, K.F. Rabe, N.C. Barnes, P.K. Jeffery (Eur Respir J 2006 Feb; 27(2):293–299).
There is variability in the distribution of inflammatory cells in bronchial tissue in chronic obstructive pulmonary disease (COPD). Better strategies for biopsy sampling of the airway mucosa may improve the capacity to show a difference between study populations where variability in distribution exists. The current authors have examined sources of biological variability in the quantification of inflammatory cells in endobronchial biopsies using immunostained samples taken from 51 subjects with COPD, with a mean forced expiratory volume in 1 second of 1.71 L, 55% predicted. The distribution of variance contributed by different sources was similar for different inflammatory cell types. For CD8+ cells, a key inflammatory cell in COPD, the largest contribution to intra-subject variability (39%) was time (i.e., 10 weeks between biopsies of placebo-treated subjects), followed by airway generation (23%), biopsy (2.5%), zone (within section; 1.4%) and section (0.4%). Power calculations demonstrated that examining one section from one biopsy, from each of two airway generations, would require a sample size of 32 subjects per group to show a difference of one doubling or halving in CD8+ cells, compared with 47 subjects per group if only one airway generation was sampled. Therefore, biopsies from more than one airway generation should be examined in order to maximise statistical power to detect a difference between study groups.
Comments.
The heterogeneity of the underlying airway inflammation of COPD is gaining greater appreciation as researchers search for novel therapies that may help certain subgroups of patients with the clinical diagnosis of COPD. Certainly it is recognized that only a subset of COPD patients respond to inhaled steroids and there are certain markers such as sputum eosinophils that predict a positive response. Gamble et al. have examined the variability of the distribution of bronchial inflammation in patients treated with placebo or cilomilast who had endobronchial biopsies collected before and after 10 weeks of treatment. The study is actually an extension of a previous study that looked at 51 GOLD stage II and III subjects mean age 63, 46 pack year history, current and ex-smokers who participated in a randomized control trial comparing cilomilast (a selective phosphodiesterase 4 inhibitor) to placebo. Biopsy specimens were analyzed for CD8+ T-lymphocytes, CD4+ T-lymphocytes, CD68+ monocyte/macrophages, neutrophils elastase (NE) and tumor necrosis factor alpha (TNFα). The two levels of endobronchial biopsies were obtained from the right lower lobe and right middle lobe carinae and from the right lower lobe subsegmental carinae. The placebo-treated group biopsies were studied for time effect by looking at the results before at 10 weeks at end of treatment phase. Zonal differences compared a region of the biopsy specimens 100 μ m deep from the reticular basement membrane versus all available subepithelial tissue. The findings of this group suggest that there is little to be gained from analyzing more than one biopsy from each of the two airway levels. The results from this paper are invaluable for assisting researchers who wish to design studies that include examination of bronchial biopsy inflammatory cell data.
Blocking Airway Mucous Cell Metaplasia by Inhibiting EGFR Antiapoptosis and IL-13 Transdifferentiation Signals; J.W. Tyner, E.Y. Kim, K. Ide, M.R. Pelletier, W.T. Roswit, J.D. Morton, J.T. Battaile, A.C. Patel, G.A. Patterson, M. Castro, M.S. Spoor, Y. You, S.L. Brody, M. J. Holtzman (J Clin Invest 2006 Feb 1; 116(2):309–321).
Epithelial hyperplasia and metaplasia are common features of inflammatory and neoplastic disease, but the basis for the altered epithelial phenotype is often uncertain. Here we show that long-term ciliated cell hyperplasia coincides with mucous (goblet) cell metaplasia after respiratory viral clearance in mouse airways. This chronic switch in epithelial behavior exhibits genetic susceptibility and depends on persistent activation of EGFR signaling to PI3K that prevents apoptosis of ciliated cells and on IL-13 signaling that promotes transdifferentiation of ciliated to goblet cells. Thus, EGFR blockade (using an irreversible EGFR kinase inhibitor designated EKB-569) prevents virus-induced increases in ciliated and goblet cells whereas IL-13 blockade (using s-IL-13Ralpha2-Fc) exacerbates ciliated cell hyperplasia but still inhibits goblet cell metaplasia. The distinct effects of EGFR and IL-13 inhibitors after viral reprogramming suggest that these combined therapeutic strategies may also correct epithelial architecture in the setting of airway inflammatory disorders characterized by a similar pattern of chronic EGFR activation, IL-13 expression, and ciliated-to-goblet cell metaplasia.
Comments.
Mucous hypersecretion contributes to airflow obstruction in several diseases including COPD, asthma and cystic fibrosis. The precise mechanism for the increased production of mucous remains poorly understood. EGFR ligands and IL-13 are capable of inducing mucous production. Tyner and colleagues demonstrate in a mouse model of virus-induced mucous hypersecretion that EGFR can inhibit ciliated cell apoptosis, which in turn allows IL-13 to stimulate transdifferentiation of these ciliated cells to goblet cells. In this model, following an acute antiviral response that clears the virus there is a subsequent post-viral response with acute activation of EGFR during epithelial repair that is then replaced by chronic activation of EGFR localized to ciliated epithelial cells. Whether these mechanisms are relevant for smoking-related goblet cell hyperplasia requires further study but may lead to novel therapies for chronic bronchitis, COPD and other airway diseases.