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1 Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado at Denver and Health Sciences Center, Denver, Colorado; 2 Division of Pulmonary and Critical Care Medicine, Indiana University School of Medicine, Indianapolis, Indiana; and 3 Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University, Nashville, Tennessee
This is the second in a series of four executive summaries of the Clinical Year in Review sessions presented at the American Thoracic Society International Conference in May, 2008. The main topics of each talk have been abstracted by the session chair based on the annotated bibliography provided by each presenter.
PULMONARY INFECTIONS IN THE IMMUNOCOMPETENT HOST
Sanjay Sethi
University of Buffalo Department of Medicine
Buffalo, New York
Dr. Sethi described recent advances and findings in three areas related to pulmonary infections in the immunocompetent host: acute exacerbations of chronic obstructive pulmonary disease (COPD), community-acquired pneumonia (CAP), and ventilator-associated pneumonia (VAP).
Acute Exacerbations of COPD
The contribution of antibiotic resistance to the major pathogens of acute exacerbations of chronic bronchitis and COPD (Haemophilus influenza, Moraxella catarrhalis, and Streptococcus pneumonia) remains unclear. In addition, randomized clinical trials (RCTs) of antibiotics are usually conducted to demonstrate equivalence for regulatory approval, and not efficacy. Therefore, most RCTs are underpowered to determine the role resistance relative to outcomes. A report from Dimopoulos and colleagues used a meta-analysis of RCTs to address this question (1). Twelve RCTs were identified that included 2,261 patients who received first-line antibiotics (amoxicillin, ampicillin, pivampicillin, trimethoprim-sulfa, and doxycycline) or second-line therapies (amoxicillin/clavulanate, macrolides, second- or third-generation cephalosporins, and fluoroquinolones) in the treatment of acute exacerbations of COPD. The data showed that first-line antibiotics were only half as effective as second-line antibiotics, with an odds ratio for treatment success of 0.51 (95% confidence interval [CI], 0.34 to 0.75). On the basis of this meta-analysis, first-line antibiotics, such as amoxicillin and related drugs, cannot be recommended for use in exacerbations of COPD.
Antibiotics are often prescribed for COPD exacerbations, but quantitative cultures of bronchoscopic protected brush samples (PSBs) have revealed significant concentrations of bacteria in the distal airways in only about 50% of affected patients. To determine the clinical predictors of bacterial infection, Soler and colleagues used PSB examination in 40 patients hospitalized for COPD (2). Significant concentrations of bacteria were seen in 45% of patients. The positive predictive value of sputum purulence was 77% and the negative predictive value was 89%. Data from this study demonstrated that patient-reported sputum purulence is a reasonable indicator of distal airway infection in COPD exacerbations. These data also suggest that purulent sputum is an important decision-making factor in determining when to use antibiotics in COPD exacerbations.
Community-acquired Pneumonia
The influence of S. pneumoniae bacteremia on outcomes of hospitalized patients with CAP has not been fully elucidated. Using a retrospective database from the Community Acquired Pneumonia Organization (CAPO) database, Bordon and coworkers conducted a retrospective analysis of an international observational study of adults with CAP (3). Their findings, derived from 1,972 patients in 43 hospitals from 12 countries, revealed that bacteremia occurred in 4.4% of patients, and these patients tended to be younger, afflicted with HIV, and were more likely to have high rates of alcohol and/or drug use. However, the authors could not detect an effect of bacteremia on time to clinical stability, length of hospital stay, or mortality due to all causes or related to CAP. Although this study was weakened by the retrospective design, the authors demonstrated that pneumococcal bacteremia is not an independent predictor of poor clinical outcomes in hospitalized adults with CAP.
Methicillin-resistant Staphylococcus aureus (MRSA) infections are major causes of morbidity and mortality. In the majority of infections, the virulence of MRSA is due to the production of a cytotoxin known as Panton-Valentine leukocidin (PVL), which is the cause of necrotic lesions involving the skin or mucosa, including necrotic hemorrhagic pneumonia. The factors predicting the mortality for the latter condition have not been identified. To address this important question, Gillet and colleagues describe the clinical course of 50 cases of PVL-producing strains of S. aureus that cause necrotizing pneumonia (4). Interestingly, only 12% of isolates were MRSA, and only 20% had any risk factors for infection or respiratory disease. The overall mortality was 56% and median survival was 10 days. Airway bleeding, erythroderma, and leukopenia were associated with mortality, whereas preexisting skin or tissue infection and pleural effusions appeared to be protective. However, even when identified, effective treatment for this pneumonia has yet to be determined.
Ventilator-associated Pneumonia
Current guidelines for the treatment of VAP recommend broad-spectrum combination antibiotics as initial therapy. However, this approach has not been validated in rigorous clinical trials, and antibiotic therapy is not without risk. To address this question, Heyland's group randomized patients with suspected VAP to monotherapy with meropenem or meropenem plus cirprofloxicin (5). Using 28-day mortality as an endpoint for the study of 740 randomized patients, the authors did not detect a difference in 28-day mortality between groups. Notably, combination therapy did not result in increased rates of super infection, colitis, or fungal growth compared with monotherapy. However, in the subgroup of patients with resistant gram-negative bacteria (8% of patients), empiric monotherapy was inadequate and associated with a trend toward higher mortality. In another study examining Psuedomonas aeruginosa VAP, Garnacho-Montero and colleagues reported that initial appropriate antibiotics resulted in a 34% mortality compared with a 73% mortality rate in patients not given appropriate treatment (6). However, selecting one appropriate antibiotic was sufficient because the mortality was not different in patients treated with one or two effective antibiotics. Collectively, these two studies suggest a strategy using a combination of antibiotics initially to increase the likelihood of appropriate coverage followed by de-escalation to a single agent once antibiotic susceptibilities are available, even if P. areuginosa is the cause of VAP.
ISSUES IN THE TRAINING OF FELLOWS AND RESIDENTS
Jess Mandel
University of California, San Diego, School of Medicine
La Jolla, California
In the United States, the Accreditation Council for Graduate Medical Education (ACGME) mandated a restriction of work hours for all medical trainees. Effective July 1, 2003, trainees could work no more than 80 hours/week, no more than 6 of 7 days per week when averaged over 4 weeks, no more than 30 continuous hours, and no more than a one in three call night schedule, and trainees were required to have at least 10 hours of rest between shifts. The rationale for these changes was recognition of medical errors as a major public health issue and a relationship between fatigue and human error in high-reliability tasks. However, there are also concerns with the reduction of residency hours specifically related to continuity of care and the potential lack of professionalism associated with the new system. In this session of the Clinical Year in Review, four general topics were discussed: trainee work hours, barriers to developing physician-scientists in pulmonary and critical care medicine, future recommendations concerning residency training and education, and knowledge of biostatistics among trainees.
To further understand the effect of the restriction of work hours, Volpp and colleagues performed an observational study of all unique Medicare patients admitted to short-term, acute-care U.S. nonfederal hospitals between July 2000 and June 2005 (7). This study specifically examined patients with one of five diagnoses: acute myocardial infarction, congestive heart failure, gastrointestinal bleeding, stroke, and general, orthopedic, or vascular surgery. The main outcome variable was death within 30 days of admission. Overall data on over 8 million patients who were admitted to one of 3,321 hospitals were examined. Adjustments were made in the analyses for 27 patient-related comorbidities, age, sex, common time trends, and hospital size. The study did not identify any positive or negative change in mortality among Medicare patients in the 2 years after work-hour changes were initiated. However, this study was unable to assess actual compliance with the work-hour restrictions. This same group of investigators performed a similar analysis on over 300,000 patients admitted to one of 131 Veterans Affairs (VA) hospitals (8). In this VA patient population, there was a significant improvement in mortality in patients with acute myocardial infarctions after the work-hour restrictions were implemented. There were no changes in mortality for the patients with surgical diagnoses in this patient population. The authors concluded that work-hour changes have had profound effects on the process of care of patients and the education of trainees. However, data from large administrative databases do not unequivocally show consistent large shifts in patient outcome as measured by mortality.
The number of physician-scientists in the area of pulmonary and critical care medicine is diminishing. To further examine this concern, Weinert and colleagues conducted a web-based survey of first-year fellows and junior faculty in pulmonary/critical care and neonatology divisions (9). A total of 46% of 1,374 individuals responded to the survey, representing 44 states and Canada. The mean age of the fellows and the junior faculty members was 33 and 38 years of age, respectively. Ninety percent of the respondents had participated in some form of research. Debt relief was considered to be only one aspect of physician-scientist recruitment. Importantly, mentors were perceived as personally supportive but less helpful in career development. Trainees wanted more information on academic career pathways, job expectations, and success rates. The authors recommended that fellowship curriculum should be modified accordingly to improve the future retention of physician-scientists in pulmonary and critical care medicine.
From 2005 to 2007, the leadership of the internal medicine community, working under the auspices of the Alliance for Academic Internal Medicine Education Redesign Task Force, convened to start to redesign education for internal medicine programs (10). They developed six recommendations that will likely have future impact on pulmonary and critical care fellowship programs:
It is likely that competency-based education will require more rigorous evaluation of trainees, and the increased emphasis on ambulatory education will result in fewer trainees available in the inpatient setting unless residency slots are significantly expanded. Hospital physician staffing, particularly in the intensive care units will need to adapt as residency training evolves.
Evidence-based medicine requires an ability to critically assess the quality of medical literature, which requires knowledge of biostatistics. The ACGME's practice-based learning and improvement competency requirements expect trainees to use the knowledge of study designs and statistical methods during their appraisal of clinical studies. Windish and colleagues administered a multiple-choice test to 277 residents in 11 residency programs, with a 76% response rate (11). General medicine fellows and faculty with advanced training in biostatistics were used to document discriminative validity. The overall mean percentage of correct answers on statistical knowledge and interpretation of results was 41.4% for the residents and 71.5% for fellows and general medicine faculty with research training. The authors concluded that residents' and fellows' knowledge of biostatistics is suboptimal, and that residency and fellowship curricula need to augment biostatistics teaching.
ASTHMA
Tina V. Hartert
Vanderbilt University School of Medicine
Nashville, Tennessee
Asthma Risk Factors
To explore risk factors for childhood asthma, Bisgaard and colleagues asked whether neonatal bacterial colonization of the hypopharynx is associated with development of recurrent wheezing and asthma (12). Microbial cultures from hypopharyngeal aspirates were prospectively evaluated in 1-month-old newborns from a birth cohort of children who were at risk for asthma and who were monitored until age 5 years. Twenty-one percent of the infants were colonized with S. pneumoniae, M. catarrhalis, H. influenzae, or a combination of these organisms; colonization with one or more of these organisms, but not colonization with S. aureus (present in 61%), was significantly associated with persistent wheeze, acute severe exacerbation of wheeze, and hospitalization for wheeze. The prevalence of asthma and the reversibility of airway resistance at age 5 were significantly increased in the children colonized neonatally with these organisms as compared with the children without such colonization (33 vs. 10% and 23 vs 18%, respectively). The authors concluded that neonates colonized in the hypopharyngeal region with S. pneumoniae, M. catarrhalis, or H. influenzae are at increased risk for recurrent wheezing and asthma. What remains to be determined is whether the bacterial colonization is the cause of asthma or is simply a marker of innate immune system dysfunction that is associated with and predisposes to asthma. Alternatively, bacterial colonization may represent a gene–environment interaction in which the bacterial colonization increases the risk of developing asthma in genetically predisposed individuals.
Asthma Prevention
Two studies published in the past year addressed the question of whether maternal vitamin D intake during pregnancy is associated with the risk of wheezing symptoms in these women's offspring. Devereux and colleagues studied 1,194 mother–infant dyads from a northeastern United States birth cohort recruited in utero with the primary objective of identifying associations between maternal diet during pregnancy and asthma and allergies in children (13). Maternal vitamin D intake was ascertained from a food frequency questionnaire completed at 32 weeks of gestation. A comparison of the highest and lowest quintiles of maternal total vitamin D intake conferred lower risks for ever-wheezing, wheezing in the previous year, and persistent wheezing at age 5. In addition, lower maternal total vitamin D intakes in pregnancy were associated with decreased bronchodilator response. No associations were observed between maternal vitamin D intakes and spirometry or exhaled nitric oxide concentrations. Camargo and colleagues studied 2,000 healthy pregnant women in Scotland (14). Maternal vitamin D intake was ascertained by food frequency questionnaire. Comparison of the highest and lowest quintiles of maternal total vitamin D intake conferred lower risks for ever-wheezing, and lower maternal intake was associated with decreased bronchodilator response. Taken together, these studies suggest that increasing maternal vitamin D intake during pregnancy is associated with decreased risk of wheeze symptoms in early childhood. Because maternal diet during pregnancy is a modifiable exposure with the potential to influence the development of asthma and allergies, further prospective randomized studies of vitamin D supplementation for asthma prevention during pregnancy are needed to determine appropriate dose and efficacy.
Asthma Clinical Trials
The Pediatric Asthma Controller Trial compared the effectiveness of three 48-week regimens in achieving asthma control in a randomized double-blind study of 285 children (ages 6–14 yr) with mild–moderate persistent asthma (15). Children were randomized to one of the following three regimens: (1) fluticasone 100 µg twice daily; (2) fluticasone 100 µg/salmeterol 50 µg in the morning and salmeterol 50 µg in the evening; or (3) montelukast 5 mg in the evening. The primary outcome was asthma control days. Fluticasone monotherapy and the fluticasone/salmeterol combination were comparable in many patient-measured outcomes, including percentage of asthma control days, but fluticasone monotherapy was superior for clinic-measured spirometry, maximum bronchodilator response, exhaled nitric oxide, and PC20 (provocative concentration in methacholine causing a 20% in FEV1). Fluticasone monotherapy was superior to montelukast for asthma control days and for all other control outcomes. Growth over 48 weeks was not statistically different among the groups. This study suggests that, in school-aged children with mild to moderate asthma, fluticasone monotherapy achieves the highest level of asthma control, without significant side effects. These findings are consistent with and support current National Heart, Lung, and Blood Institute Expert Panel Report 3 guidelines and recommendations, which can be accessed at http://www.nhlbi.nih.gov/guidelines/asthma/.
In a second clinical trial published in the past year, Peters and colleagues addressed the question of whether patients with mild persistent asthma that is well controlled with the use of twice-daily inhaled corticosteroids can receive a step-down treatment with once-daily montelukast or once-daily fluticasone propionate plus salmeterol compared with a third study arm of continued twice-daily fluticasone propionate (16). Treatment in the three arms of the study was administered for 16 weeks in a double-blind manner in 500 patients, with the primary outcome being the time to treatment failure (defined as hospitalization, urgent care visit, defined changes in FEV1 or morning peak expiratory flow or rescue β-agonist use, or refusal to continue because of satisfaction or safety concerns). Approximately 20% of patients in the continued fluticasone or fluticasone plus salmeterol arms had treatment failure, compared with 30.3% of subjects in the montelukast arm. The asthma symptom–free days were similar across the three groups. In summary, fluticasone 100 µg twice daily and fluticasone 100 µg/salmeterol 50 µg once daily both provided similar asthma control and were superior to once-daily montelukast in this patient population. These strategies offer the benefits of a lower inhaled corticosteroid dose, and the once-daily dosing regimen may improve compliance. However, several caveats should be noted. First, it should be noted that the inhaled corticosteroid/long-acting β-agonist combination is not currently approved by the U.S. Food and Drug Administration for once-daily dosing. Second, switching from twice-daily low-dose inhaled corticosteroids to a once-daily inhaled corticosteroid/long-acting β-agonist combination is not consistent with current national guidelines. Mild persistent asthma is not an indication for combination therapy with inhaled corticosteroids and long-acting inhaled β2-agonists in the new Expert Panel Report 3 in light of the recent black box warning concerning the increased risk of severe asthma exacerbations and death associated with long-acting β-agonist use. The current study was not cited in the Expert Panel Report 3, and may not have been published in time for incorporation into the report.
In a study of bronchial thermoplasty for treatment of moderate to severe asthma, Cox and colleagues studied 112 subjects who had been treated with inhaled corticosteroids and long-acting β2-adrenergic agonists (LABAs) and in whom asthma control was impaired when the LABAs were withdrawn (17). Subjects were randomized to either bronchial thermoplasty, involving a radiofrequency current applied to the walls of the central airways, or a control group. The mean rate of mild exacerbations, as compared with baseline, was reduced in the bronchial thermoplasty group but was unchanged in the control group. At 12 months, there were significantly greater improvements in the bronchial thermoplasty group in morning peak expiratory flow, quality-of-life scores, percentage of symptom-free days, symptom scores, and number of puffs of rescue medication required. Values for airway responsiveness and FEV1 did not differ significantly between the two groups. Adverse events immediately after treatment were more common in the bronchial thermoplasty group, but were similar between groups during the period from 6 weeks to 12 months after treatment. This study provides the best data to date to suggest that bronchial thermoplasty in subjects with moderate or severe asthma results in an improvement in asthma control. However, the mechanisms underlying the therapeutic effects of bronchial thermoplasty in asthma are still not fully understood. Bronchial thermoplasty only ablates airway myocytes in larger bronchi accessible to treatment, and involves considerable effort and risk, with notable short-term adverse effects.
Asthma Clinical Trials/Pathogenesis
Wenzel and colleagues conducted two independent randomized, double-blind, placebo-controlled, parallel-group, phase 2a clinical trials of pitrakinra, an IL-4 variant that targets allergic Th2 inflammation by inhibiting the binding of IL-4 and IL-13 to IL-4R
receptor complexes (18). Patients with atopic asthma were treated with pitrakinra or placebo via two routes. In study 1, patients received pitrakinra (n = 12) or placebo (n = 12) by subcutaneous injection once daily; in study 2, patients received either pitrakinra (n = 16) or placebo (n = 16) by inhaled nebulization twice daily. The primary outcome was late-phase response to inhaled allergen challenge 4 weeks after therapy. In study 1, there was a larger maximum percentage decrease in FEV1 after allergen challenge in the placebo group, although the difference was not significant. In study 2, there was a significantly larger drop in the average percentage decrease in FEV1 after allergen challenge in the placebo group. There were fewer asthma-related adverse events and fewer adverse events requiring β-agonist rescue after subcutaneous administration of pitrakinra than with placebo. These encouraging phase 2a clinical trials suggest that treatment targeted at inhibition of IL-4 and IL-13 could diminish the symptoms of asthma. As pointed out in the accompanying editorial by Holt and Sly, this recombinant human IL-4 variant also resulted in accelerated recovery from the initial fall in lung function after allergen challenge (19). Follow-up trials not limited to the model of the late-phase response are needed to determine the efficacy in patients with asthma on disease control and modification.
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Jadwiga A. Wedzicha
Academic Unit of Respiratory Medicine
University College London
London, United Kingdom
Several topics related to COPD were discussed at this session. Initially, articles examining the epidemiology of COPD were presented in detail. Two articles reported global variability in the burden of COPD (20, 21). Both articles revealed a very high prevalence of COPD in South African males, and reported global prevalence rates that were higher than previously reported. In the article by Buist and colleagues, the global prevalence of patients with COPD stages 2–4 was estimated to be 10.1% overall; 11.8% for men and 8.5% for women (20). Age of the patient and cigarette smoking status did not fully explain the variation in disease prevalence. An article from China supported the observation that other factors influence the susceptibility to develop COPD. In a large cohort study, the authors reported an association between risk of COPD and self-reported exposure to passive smoking at home and in the work environment, with an odds ratio of 1.48 for high exposure equivalent to 40 hours/week for 5 years (22). In addition, there was a significant association between reported respiratory symptoms and increasing passive smoking exposure. The authors estimated that 1.9 million excess deaths from COPD among never-smokers may be attributable to passive smoking in China. Exposure to biomass fuels is another environmental factor that may increase susceptibility to COPD. Globally, about 3 billion people may be using biomass fuels for energy. In another Chinese study, investigators examined the prevalence of COPD in two communities in Guangdong province and measured the association between COPD and indoor biomass fuel air pollution (23). They performed a cluster disproportional random sampling survey of individuals older than 40 years in both urban and rural areas. Measurements of indoor and outdoor pollutants were collected in a random sample of dwellings. The use of biomass fuel was higher in the rural areas (88.1%) compared with the urban areas (0.7%). The overall prevalence of COPD in the two areas was 9.4%. However, the prevalence of COPD was higher in rural areas at 12% when compared with 7.4% in urban areas. Of importance, COPD in nonsmoking women was 7.4% in rural areas and only 2.5% in urban areas. This study demonstrates that biomass fuels contribute to the increased prevalence of COPD in developing countries.
Inflammation and oxidative stress are associated with decreased lung function. Statins are known to have antiinflammatory and antioxidant properties and therefore may have an effect on lung function. The next study examined 803 elderly men enrolled in the Normative Aging Study who had lung function (FEV1 and FVC) measured two to four times between 1995 and 2005 (24). In addition to other variables, subjects reported statin use and smoking history at each visit. For those patients not using statins, the estimated annual decline in FEV1 was 23.9 ml, compared with only 10.9 ml in those individuals taking statins. Within each smoking category (never-smoker, long-time quitter [>10 yr], recent quitter [<10 yr], and current smoker), the effects of statins on lung function remained beneficial. However, the size of the improvement in the decline rate varied among the smoking groups. Similar results were also observed for the decline in the FVC. In addition to smoking, lung function measured in early adulthood is one of the strongest predictors of COPD. The next study enrolled infants at birth who were prospectively followed to examine whether lung function in early adulthood is determined by airway function measured shortly after birth (25). Measurements were obtained in 123 of participants at least once at ages 11, 16, and 22 years. Participants who had an FRC obtained during infancy in the lowest quartile also had lower values of FEV1/FVC, FEF25–75% (forced expiratory flow, midexpiratory phase), and FEV1 up to age 22, after adjustment for height, weight, and age. This article demonstrates the close association between lung function in infancy and these individuals' lung function as an adolescent and early adult, and supports the hypothesis that factors affecting lung function in utero may determine the degree of lung function attained in adulthood.
The next study examined the causes of death in patients with COPD who were enrolled into the TORCH (Towards a Revolution in COPD Health) study (26). The primary cause of death in these patients was attributed to respiratory failure in only 35% of the patients, cardiovascular events in 26% of the patients, and lung cancer in 14% of the patients. In another cohort of patients with COPD who were hospitalized for an acute exacerbation of their disease, McGhan and colleagues reported a 1- and 5-year risk of death of 21 and 55%, respectively (27). The risk of death increased in association with the number of previous hospitalizations. Other risk factors for rehospitalization that were identified were age, male sex, and previous comorbidities. As noted above, cardiovascular disease is a major cause of death among patients with COPD. Although β-blockers improve cardiovascular outcomes, patients with COPD often do not receive these medications due to concerns about possible adverse pulmonary effects. The next study identified factors associated with β-blocker use and mortality in patients with COPD (28). β-Blocker use was associated with a reduction in mortality in 825 patients with COPD who required hospitalization based on administrative data. Several studies over the last year examined the role of biomarkers on COPD prognosis. One study demonstrated that brain natriuretic peptide levels were higher in patients with COPD who required intensive care unit admission, but these acute measurements of brain natriuretic peptide did not predict 6-month and 2-year outcomes (29). In another article that was discussed, elevated serum amyloid A concentrations were associated with the severity of the acute exacerbation of COPD (30).
Lung volume reduction surgery (LVRS) provides functional and mortality benefits to a select group of patients with COPD. The effects of LVRS on acute exacerbations of COPD have not been previously examined. The next study examined the effect and mechanism of LVRS on COPD exacerbations by comparing the medical and surgical cohorts enrolled into the National Emphysema Treatment Trial (31). In this RCT, the surgical patients experienced a 30% reduction in exacerbation frequency after randomization when compared with the medical patients. This effect was greatest in those surgical subjects with the largest postoperative improvement in FEV1.
The role of tiotroprium and combination therapy with salmeterol and fluticasone for patients with COPD was examined in several clinical trials performed last year. The first study by Powrie and colleagues was an RCT of tiotroprium compared with placebo (32). The article demonstrated a decrease in the frequency of acute exacerbations in patients with COPD who received tiotroprium. This effect occurred despite the fact that tiotroprium had no significant effect on serum levels of a variety of inflammatory markers. The next clinical trial compared the relative efficacy of tiotroprium and combination therapy with salmeterol and fluticasone in preventing exacerbations and related outcomes in patients with severe COPD (33). A total of 1,323 patients were randomized into this trial. The probability of withdrawing from the study was 29% greater in the tiotroprium compared with the salmeterol/fluticasone group. There was no difference in the annual exacerbation rate between the two therapies. Similar to the TORCH study, treatment with salmeterol/fluticasone was associated with an increased risk of reported pneumonia. Patients who were randomized to salmeterol/fluticasone and who experienced exacerbations required fewer oral corticosteroids. Patients who were randomized to tiotroprium and who had exacerbations required fewer antibiotics. However, the St. George's Respiratory Questionnaire total score was statistically lower at 2 years in the salmeterol/fluticasone group compared with tiotroprium. As a result of these clinical trials, Aaron and colleagues published an article concerning study design issues related to trials for patients with COPD (34). They recommended that future trials should include blinded adjudication of exacerbations to ensure events are independent, an intention-to-treat analysis should be used, and these trials should use time-weighted intention-to-treat analyses.
FOOTNOTES
Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form June 18, 2008; accepted in final form June 23, 2008)
REFERENCES
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