Robert A. Wise

Long-term effects of budesonide or nedocromil in children with asthma

BACKGROUND Antiinflammatory therapies, such as inhaled corticosteroids or nedocromil, are recommended for children with asthma, although there is limited information on their long-term use. METHODS We randomly assigned 1041 children from 5 through 12 years of age with mild-to-moderate asthma to receive 200 microg of budesonide (311 children), 8 mg of nedocromil (312 children), or placebo (418 children) twice daily. We treated the participants for four to six years. All children used albuterol for asthma symptoms. RESULTS There was no significant difference between either treatment and placebo in the primary outcome, the degree of change in the forced expiratory volume in one second (FEV1, expressed as a percentage of the predicted value) after the administration of a bronchodilator. As compared with the children assigned to placebo, the children assigned to receive budesonide had a significantly smaller decline in the ratio of FEV1 to forced vital capacity (FVC, expressed as a percentage) before the administration of a bronchodilator (decline in FEV1:FVC, 0.2 percent vs. 1.8 percent). The children given budesonide also had lower airway responsiveness to methacholine, fewer hospitalizations (2.5 vs. 4.4 per 100 person-years), fewer urgent visits to a caregiver (12 vs. 22 per 100 person-years), greater reduction in the need for albuterol for symptoms, fewer courses of prednisone, and a smaller percentage of days on which additional asthma medications were needed. As compared with placebo, nedocromil significantly reduced urgent care visits (16 vs. 22 per 100 person-years) and courses of prednisone. The mean increase in height in the budesonide group was 1.1 cm less than in the placebo group (22.7 vs. 23.8 cm, P=0.005); this difference was evident mostly within the first year. The height increase was similar in the nedocromil and placebo groups. CONCLUSIONS In children with mild-to-moderate asthma, neither budesonide nor nedocromil is better than placebo in terms of lung function, but inhaled budesonide improves airway responsiveness and provides better control of asthma than placebo or nedocromil. The side effects of budesonide are limited to a small, transient reduction in growth velocity.

The Effects of a Smoking Cessation Intervention on 14.5-Year Mortality: A Randomized Clinical Trial

Context Although there are many health benefits for smokers who stop smoking, we still lack evidence from randomized, controlled trials that smoking cessation programs reduce mortality. Contribution In this randomized, controlled trial of a 10-week-long smoking cessation intervention in 5887 smokers with asymptomatic airway obstruction, 14-year mortality rates were higher in the usual care group than in the smoking cessation group (hazard ratio, 1.18 [95% CI, 1.02 to 1.37]). The mortality benefit was greatest among the 21.7% of the intervention group who actually managed to quit smoking. Implications Smoking cessation programs substantially reduce mortality even when only a minority of patients stop smoking. The Editors Smoking cessation almost certainly has beneficial effects on subsequent mortality (1). However, the strongest support for this assertion comes from cohort studies, where smokers and quitters were self-selected. Results from randomized trials, which avoid the selection issue, have largely been disappointing because mortality benefits have not been clear or have not been clearly attributable to smoking cessation (1). The Lung Health Study (LHS) was a randomized clinical trial of smoking cessation and inhaled bronchodilator (ipratropium) therapy in smokers 35 to 60 years of age who did not consider themselves ill but had evidence of mild to moderate airway obstruction (2). Individuals with serious disease, hypertension, obesity, or excessive alcohol intake were excluded. The primary research questions were whether a smoking cessation program and use of inhaled ipratropium would decrease the rate of decline of lung function and would affect mortality and morbidity over 5 years. These results have been reported elsewhere (3, 4). The smoking cessation program was associated with cumulative reduced decline in lung function (FEV1) that was largest in participants who stopped smoking early in the study; inhaled ipratropium produced a small noncumulative increase in FEV1 that disappeared when the drug was withdrawn (3). Intention-to-treat analysis after 5 years did not reveal differences in morbidity or mortality among treatment groups (4), although subgroup analysis showed that smoking cessation was associated with significant reductions in fatal or nonfatal cardiovascular disease and coronary heart disease. This paper reports the effects of the study intervention on mortality in LHS participants 14.5 years after randomization. Methods The design of the LHS has been described in detail elsewhere (2). The participants, all volunteers, were smokers who did not consider themselves ill but had evidence of airway obstruction and little evidence of other disease. Researchers recruited participants from the community using a wide variety of techniques (5). In 10 clinical centers, 5887 participants were randomly assigned to 3 groups. Two special intervention groups received an intensive 10-week smoking cessation program. Briefly, the cessation intervention consisted of a strong physician message and 12 two-hour group sessions, using behavior modification and nicotine gum. Quitters entered a maintenance program that stressed coping skills. One special intervention group also received ipratropium, while the other received a placebo inhaler. A third group received usual care. About 75% of the original participants were followed continuously for the subsequent 10 years by biannual telephone contacts and 1 clinic visit at approximately 11 to 12 years after randomization (6). Telephone contacts served to check smoking status, morbidity, and mortality and were not part of the intervention. All study participants provided written informed consent for the original LHS before beginning the study. The consent documents stated that smoking increases the risk for chronic obstructive pulmonary disease, respiratory tract cancer, and cardiovascular disease and that smoking cessation would decrease such risks. Additional written informed consent was obtained from persons who participated in the biannual telephone calls. Institutional review boards at each of the 10 clinical centers and the coordinating center approved the study design and consent documents. When biannual phone calls revealed a participant death, staff attempted to collect death certificates, autopsy reports, relevant medical records, and interviews with attending physicians or eyewitnesses. An independent mortality and morbidity review board examined these data and classified causes of death. In addition, a National Death Index review provided date and cause of death for all U.S. study participants through the end of 2001. Vital status at 31 December 2001 or 14.5 years, whichever was earlier, was successfully determined for 98.3% of all participants; missing individuals were Canadians who had been lost to follow-up and were not accessible through the National Death Index. Mortality end points were classified in 7 categories: coronary heart disease, cardiovascular disease including coronary heart disease, lung cancer, other cancer, respiratory disease excluding lung cancer, other, and unknown. The other category included but was not limited to liver disease, kidney disease, sepsis, accidents, suicide, and AIDS. Analyses were performed on an intention-to-treat basis, comparing the special intervention group with the usual care group. The special intervention group was a combination of the groups originally assigned to receive inhaled ipratropium or placebo therapy. Both of these groups, which were very similar at baseline, received the smoking cessation program and exhibited similar rates of smoking cessation (3). Participants were also divided into 3 groups according to smoking history during the initial 5 years of the trial. Sustained quitters were participants who stopped smoking in the first year after randomization and maintained biochemically validated abstinence (3) throughout follow-up. Continuing smokers were participants who reported smoking at all follow-up visits. Intermittent quitters were participants who reported smoking at some but not all of their follow-up visits or during the time between visits. Statistical Analysis Baseline differences between the special intervention and usual care groups were tested by using t-tests for continuous variables and chi-square statistics for categorical variables. Cause-specific death rates and times to events were analyzed by using the KaplanMeier product-limit method (7). Survival was compared among groups by using the log-rank test. Hazard ratios and adjusted analyses were obtained by using the Cox proportional hazards model. Interactions were assessed by comparing hierarchically related proportional hazards models. All P values result from 2-sided tests; no adjustments were made for multiple comparisons. Role of the Funding Source This study was funded by a contract and grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health. The funding source had a role in the design of the study and approved the manuscript before it was submitted for publication. Results Baseline characteristics of LHS participants are shown in Table 1. Most were middle-aged; smoked heavily; and had substantial smoking histories, airway obstruction (FEV1FVC ratio 70%), and borderline low FEV1 values. On average, participants were normotensive and had normal body mass indices. Most participants were of white ethnicity; 37% were women. The average participant had some postsecondary education and did not drink heavily. The special intervention and usual care groups did not significantly differ at baseline, except in percentage of participants who were married, which was higher in the special intervention group (P= 0.04). Smoking status after the first 5 years differed significantly between treatment groups (P 0.001). Among special intervention participants and usual care participants, respectively, 21.7% and 5.4% were sustained quitters, 29.3% and 23.3% were intermittent quitters, and 49.0% and 71.3% were continuing smokers. Table 1. Baseline Characteristics of Lung Health Study Participants There were 731 known deaths among LHS participants, as shown in Table 2. Lung cancer was the most common cause of death (n= 240 [33%]). Coronary heart disease accounted for 77 deaths (10.5%), and cardiovascular disease including coronary heart disease accounted for 163 deaths (22%). One hundred fifty-four participants (21%) died of cancer of organs other than the lung. Deaths due to respiratory disease other than cancer were relatively uncommon (n= 57 [7.8%]). The cause of death was unknown in only 17 participants (2.3%). Mortality did not significantly differ between the special intervention groups originally assigned to ipratropium or placebo (Table 2). Table 2. Causes of Death by Treatment Group Figure 1 shows all-cause survival rates in the 2 treatment groups. Death rates were significantly higher in the usual care group than in the special intervention group (10.38 per 1000 person-years vs. 8.83 per 1000 person-years; P= 0.03). The hazard ratio for mortality in the usual care group was 1.18 (95% CI, 1.02 to 1.37) compared with the special intervention group. Figure 2 shows categorical causes of death in the 2 treatment groups. In all categories except other, death rates were higher in the usual care group than in the special intervention group, but the difference was significant only for deaths from respiratory diseases not related to lung cancer (1.08 per 1000 person-years vs. 0.56 per 1000 person-years; P= 0.01). Figure 1. All-cause 14.5-year survival. P Figure 2. Mortality rates at 14.5 years by cause. When survival was analyzed according to smoking habit, it differed significantly between groups (P< 0.001), even after adjustment for baseline differences (data not shown). Mortality was 6.04 per 1000 person-years in sustained quitters, 7.77 per 1000 person-years in intermittent quitters, and 11.09 per 1000 p

Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease

BACKGROUND Chronic obstructive pulmonary disease (COPD) results from a progressive decline in lung function, which is thought to be the consequence of airway inflammation. We hypothesized that antiinflammatory therapy with inhaled corticosteroids would slow this decline. METHODS We enrolled 1116 persons with COPD whose forced expiratory volume in one second (FEV1) was 30 to 90 percent of the predicted value in a 10-center, placebo-controlled, randomized trial of inhaled triamcinolone acetonide administered at a dose of 600 microg twice daily. The primary outcome measure was the rate of decline in FEV1 after the administration of a bronchodilator. The secondary outcome measures included respiratory symptoms, use of health care services, and airway reactivity. In a substudy of 412 participants, we measured bone density in the lumbar spine and femur at base line and one and three years after the beginning of treatment. RESULTS The mean duration of follow-up was 40 months. The rate of decline in the FEV1 after bronchodilator use was similar in the 559 participants in the triamcinolone group and the 557 participants in the placebo group (44.2+/-2.9 vs. 47.0+/-3.0 ml per year, P= 0.50). Members of the triamcinolone group had fewer respiratory symptoms during the course of the study (21.1 per 100 person-years vs. 28.2 per 100 person-years, P=0.005) and had fewer visits to a physician because of a respiratory illness (1.2 per 100 person-years vs. 2.1 per 100 person-years, P=0.03). Those taking triamcinolone also had lower airway reactivity in response to methacholine challenge at 9 months and 33 months (P=0.02 for both comparisons). After three years, the bone density of the lumbar spine and the femur was significantly lower in the triamcinolone group (P < or = 0.007). CONCLUSIONS Inhaled triamcinolone does not slow the rate of decline in lung function in people with COPD, but it improves airway reactivity and respiratory symptoms and decreases the use of health care services for respiratory problems. These benefits should be weighed against the potential long-term adverse effects of triamcinolone on bone mineral density.

Strategies to Prevent Central Line-Associated Bloodstream Infections in Acute Care Hospitals

Previously published guidelines are available that provide comprehensive recommendations for detecting and preventing healthcare-associated infections. The intent of this document is to highlight practical recommendations in a concise format designed to assist acute care hospitals in implementing and prioritizing their central line–associated bloodstream infection (CLABSI) prevention efforts. Refer to the Society for Healthcare Epidemiology of America/Infectious Diseases Society of America “Compendium of Strategies to Prevent Healthcare-Associated Infections” Executive Summary and Introduction and accompanying editorial for additional discussion.1. Patients at risk for CLABSIs in acute care facilitiesa. Intensive care unit (ICU) population: The risk of CLABSI in ICU patients is high. Reasons for this include the frequent insertion of multiple catheters, the use of specific types of catheters that are almost exclusively inserted in ICU patients and associated with substantial risk (eg, arterial catheters), and the fact that catheters are frequently placed in emergency circumstances, repeatedly accessed each day, and often needed for extended periods.b. Non-ICU population: Although the primary focus of attention over the past 2 decades has been the ICU setting, recent data suggest that the greatest numbers of patients with central lines are in hospital units outside the ICU, where there is a substantial risk of CLABSI.2. Outcomes associated with hospital-acquired CLABSIa. Increased length of hospital stayb. Increased cost; the non-inflation-adjusted attributable cost of CLABSIs has been found to vary from 29,000 per episode

Cyclophosphamide is associated with pulmonary function and survival benefit in patients with scleroderma and alveolitis.

Interstitial lung disease is the major cause of death in patients with systemic sclerosis (scleroderma) (1). Pathologic studies of early disease show inflammation in the pulmonary interstitium that spills into alveolar spaces (2). Bronchoalveolar lavage fluid obtained from patients with scleroderma who have lung inflammation (alveolitis) may contain increased numbers of total cells, T cells, neutrophils, eosinophils, and mast cells (3-7). Alveolitis has been associated with subsequent deterioration of pulmonary function in scleroderma (3, 4). Silver and colleagues (3) tested the theory that suppressing alveolitis with cyclophosphamide may prevent loss of pulmonary function. Both oral (3, 8-10) and intravenous cyclophosphamide (11) have been reported to be beneficial. Previous studies included small numbers of patients treated with cyclophosphamide (3, 8-11) or no concurrently followed groups of untreated patients with alveolitis or patients without alveolitis (3, 8, 10, 11). In some studies, no attempt was made to diagnose lung inflammation in all patients; it was therefore not clear how many patients were at risk for deterioration of pulmonary function (9, 10). We performed a retrospective analysis of pulmonary function and survival in patients with scleroderma and alveolitis, as identified by using bronchoalveolar lavage or lung biopsy. The cohort includes patients with alveolitis who were and those who were not treated with cyclophosphamide and patients without alveolitis. Methods Patients We included patients seen at the Johns Hopkins and University of Maryland Scleroderma Center between March 1991 and December 1998 who met classification criteria for scleroderma (12) and had pulmonary function tests and bronchoalveolar lavage or lung biopsy done during workup for alveolitis. To be included, patients had to be followed until death or until at least one set of follow-up pulmonary function tests was done a minimum of 6 months after bronchoalveolar lavage or lung biopsy. Patients were categorized as having limited or diffuse cutaneous systemic sclerosis (13). Disease duration was defined as the number of months from the first symptom that was clearly attributable to scleroderma (14). Significant renal involvement was defined as new or worsening hypertension associated with an increase in serum creatinine concentration to greater than 150% of the baseline value. Pulmonary artery pressures of more than 35 mm Hg, as estimated by Doppler echocardiography, were considered high. Pulmonary Function Tests In most patients, forced vital capacity (FVC) and carbon monoxide diffusing capacity were measured in the Hopkins Bayview Pulmonary Function Laboratory by using standard procedures (15, 16) under the supervision of Dr. Wise. Normal values were derived from those in published articles by Goldman and Becklake (17) and Burrows and associates (18). Normal values on tests done elsewhere were consistent with values in this laboratory; thus, no adjustments were made. Bronchoalveolar Lavage Bronchoalveolar lavage was done as described elsewhere (19). Cell counts were obtained by using a hemocytometer. Cytocentrifuge slides of cells were stained by using a modified Giemsa stain. Cell differential was performed on 500 cells; inflammation was indicated if neutrophils were more than 3.0% of total cells or eosinophils were more than 2.2% of total cells. These cutoff values are 3 SDs above the mean of those in controls in our laboratory and are consistent with published reports (20). All patients gave informed written consent for bronchoalveolar lavage or lung biopsy. Eighty patients had testing solely for clinical indications, which included dyspnea on exertion and, usually, restrictive lung disease on pulmonary function tests. Twenty-three patients had bronchoalveolar lavage as part of a research protocol that was approved by the institutional review boards at the Johns Hopkins School of Medicine and the University of Maryland School of Medicine. These 23 patients had disease duration of less than 3 years and some dyspnea on exertion. That research protocol was separate from any treatment decision and from the current retrospective analysis of the clinical course of patients in our center, whose lung inflammation status was known. Cyclophosphamide Therapy The initial daily dose of oral cyclophosphamide was 1 to 1.5 mg/kg of body weight. The daily dose was increased as tolerated, usually in increments of 25 mg every 3 to 4 weeks, up to 2 mg/kg per day; a goal was to avoid neutropenia. Intravenous cyclophosphamide was administered monthly, with intravenous hydration, in doses of 800 to 1400 mg for 6 to 9 months. Statistical Analysis Statistical analyses were done by using StatView 5 software (SAS Institute, Inc., Cary, North Carolina). Repeated-measures analysis of variance was used to compare the rate of change in lung function over time between pulmonary function tests in different patient groups. The CoxMantel log-rank test was used to test differences in survival (21). Results Patient Groups We included 103 patients in our study. Four more patients, none of whom had alveolitis, met the inclusion criteria but were lost to follow-up. Evaluation for lung inflammation was done by bronchoalveolar lavage in 94 patients and lung biopsy in 9 patients. Sixty-nine patients had alveolitis and 34 patients did not. Of the patients with alveolitis, 39 received cyclophosphamide and 30 did not. The judgment to treat was made by consensus among Dr. White or Dr. Wigley, Dr. Wise, the patient, and the referring physician. Thirty-five patients received oral cyclophosphamide; 4 received intravenous cyclophosphamide because of the preference of the referring physician. As documented in the chart, the most common reason why patients did not receive cyclophosphamide was the judgment that alveolitis was mild and that close follow-up with or without prednisone therapy might be adequate (18 patients). Other reasons were patient unwillingness to take cyclophosphamide (8 patients), unwillingness of the referring physician to give cyclophosphamide (2 patients), and active substantial renal involvement (2 patients). The median daily dose of oral cyclophosphamide was 100 mg/d (25th, 75th percentiles, 81.5, 150 mg/d). The median duration of therapy was 10.8 months (25th, 75th percentiles, 6.5, 14.5 months). Four patients (10%) were hospitalized for infection while receiving cyclophosphamide, and two developed hemorrhagic cystitis (5%). Alopecia prompted one patient (3%) to wear a wig. The two groups of patients with alveolitis were similar in age, sex, ethnicity, disease type, disease duration, smoking status, pulmonary hypertension, antiScl 70 antibodies, renal involvement, bronchoalveolar lavage for research purposes, receipt of prednisone therapy, and prednisone dose (P >0.2 for all comparisons) (Table 1). Compared with untreated patients with alveolitis, patients who received cyclophosphamide had shorter follow-up of pulmonary function before undergoing bronchoalveolar lavage or lung biopsy (mean difference, 4.1 months [95% CI, 4.5 to 12.9 months]). Follow-up after bronchoalveolar lavage or lung biopsy and total follow-up of pulmonary function did not differ among the three patient groups (P >0.2, MannWhitney test) (Table 1). Table 1. Patient Characteristics At the time of bronchoalveolar lavage or lung biopsy, most patients with alveolitis had moderate to severe restrictive lung disease and severe impairment in gas transfer (Table 1). Compared with cyclophosphamide-treated patients, untreated patients with alveolitis had higher FVC (mean difference, 0.15 L [CI, 0.02 to 0.65 L] and 5.6% of the predicted value [CI, 2.1% to 13.9%]) (Table 1). Compared with untreated patients with alveolitis, cyclophosphamide-treated patients had a higher percentage of neutrophils in bronchoalveolar lavage fluids (Table 1) (mean difference, 1.5% [CI, 1.9% to 5.0%]) but similar total cell counts (cells/mL) and percentages of eosinophils and lymphocytes. Medically Meaningful Changes in Forced Vital Capacity and Carbon Monoxide Diffusing Capacity Our two primary outcomes were medically meaningful changes in FVC and carbon monoxide diffusing capacity. Results of pulmonary function tests done at the time of bronchoalveolar lavage or biopsy were compared with the results of the last tests done. A good outcome was defined as improvement (increase of 10% or more) or stabilization in values, and a bad outcome was defined as worsening (decrease of 10% or more) pulmonary function values or death. These criteria were defined before data analyses were done and were chosen because within-individual variation in pulmonary function results may be as high as 10%, although it is usually closer to 3% to 5% in persons with experience in taking pulmonary function tests (22). Patients who received cyclophosphamide were more likely than untreated patients with alveolitis to have a good outcome in FVC (72% and 23%; relative risk, 2.5 [CI, 1.5 to 4.1]) (Table 2). Treated patients had a better outcome in diffusing capacity than untreated patients (49% and 27%; relative risk, 1.5 [1.0 to 2.2]) (Table 2). Table 2. Medically Meaningful Changes in Pulmonary Function Changes in Pulmonary Function Test Results over Time Additional analyses examined absolute changes in the FVC and carbon monoxide diffusing capacity. Both groups of patients with alveolitis had similar decreases in FVC and carbon monoxide diffusing capacity before bronchoalveolar lavage or biopsy was done (Table 3). The rates of change in these variables before bronchoalveolar lavage or biopsy did not differ between the two groups (P >0.2 for all comparisons, repeated-measures analysis of variance). Table 3. Mean Differences in Pulmonary Function over Time After bronchoalveolar lavage or biopsy, patients with alveolitis who did not receive cyclophosphamide had further decreases in FVC (mean difference, 0.28 L [CI, 0.41 to 0.16 L] and 7.1% o

Ascertainment of cause-specific mortality in COPD: operations of the TORCH Clinical Endpoint Committee

Background: TORCH (Towards a Revolution in COPD Health) is an international multicentre, randomised, placebo-controlled clinical trial of inhaled fluticasone propionate/salmeterol combination treatment and its monotherapy components for maintenance treatment of moderately to severely impaired patients with chronic obstructive pulmonary disease (COPD). The primary outcome is all-cause mortality. Cause-specific mortality and deaths related to COPD are additional outcome measures, but systematic methods for ascertainment of these outcomes have not previously been described. Methods: A Clinical Endpoint Committee (CEC) was tasked with categorising the cause of death and the relationship of deaths to COPD in a systematic, unbiased and independent manner. The key elements of the operation of the committee were the use of predefined principles of operation and definitions of cause of death and COPD-relatedness; the independent review of cases by all members with development of a consensus opinion; and a substantial infrastructure to collect medical information. Results: 911 deaths were reviewed and consensus was reached in all. Cause-specific mortality was: cardiovascular 27%, respiratory 35%, cancer 21%, other 10% and unknown 8%. 40% of deaths were definitely or probably related to COPD. Adjudications were identical in 83% of blindly re-adjudicated cases (κ = 0.80). COPD-relatedness was reproduced 84% of the time (κ = 0.73). The CEC adjudication was equivalent to the primary cause of death recorded by the site investigator in 52% of cases. Conclusion: A CEC can provide standardised, reliable and informative adjudication of COPD mortality that provides information which frequently differs from data collected from assessment by site investigators.

C-reactive protein and mortality in mild to moderate chronic obstructive pulmonary disease

Background: Although C-reactive protein (CRP) levels are increased in chronic obstructive pulmonary disease (COPD), it is not certain whether they are associated with adverse clinical outcomes. Methods: Serum CRP levels were measured in 4803 participants in the Lung Health Study with mild to moderate COPD. The risk of all-cause and disease specific causes of mortality was determined as well as cardiovascular event rates, adjusting for important covariates such as age, sex, cigarette smoking, and lung function. Cardiovascular events were defined as death from coronary heart disease or stroke, or non-fatal myocardial infarction or stroke requiring admission to hospital. Results: CRP levels were associated with all-cause, cardiovascular, and cancer specific causes of mortality. Individuals in the highest quintile of CRP had a relative risk (RR) for all-cause mortality of 1.79 (95% confidence interval (CI) 1.25 to 2.56) compared with those in the lowest quintile of CRP. For cardiovascular events and cancer deaths the corresponding RRs were 1.51 (95% CI 1.20 to 1.90) and 1.85 (95% CI 1.10 to 3.13), respectively. CRP levels were also associated with an accelerated decline in forced expiratory volume in 1 second (p<0.001). The discriminative property of CRP was greatest during the first year of measurement and decayed over time. Comparing the highest and lowest CRP quintiles, the RR was 4.03 (95% CI 1.23 to 13.21) for 1 year mortality, 3.30 (95% CI 1.38 to 7.86) for 2 year mortality, and 1.82 (95% CI 1.22 to 2.68) for ⩾5 year mortality. Conclusions: CRP measurements provide incremental prognostic information beyond that achieved by traditional markers of prognosis in patients with mild to moderate COPD, and may enable more accurate detection of patients at a high risk of mortality.

Efficacy of Esomeprazole for Treatment of Poorly Controlled Asthma

BACKGROUND Gastroesophageal reflux is common among patients with asthma but often causes mild or no symptoms. It is not known whether treatment of gastroesophageal reflux with proton-pump inhibitors in patients who have poorly controlled asthma without symptoms of gastroesophageal reflux can substantially improve asthma control. METHODS In a parallel-group, double-blind trial, we randomly assigned 412 participants with inadequately controlled asthma, despite treatment with inhaled corticosteroids, and with minimal or no symptoms of gastroesophageal reflux to receive either 40 mg of esomeprazole twice a day or matching placebo. Participants were followed for 24 weeks with the use of daily asthma diaries, spirometry performed once every 4 weeks, and questionnaires that asked about asthma symptoms. We used ambulatory pH monitoring to ascertain the presence or absence of gastroesophageal reflux in the participants. The primary outcome was the rate of episodes of poor asthma control, as assessed on the basis of entries in asthma diaries. RESULTS Episodes of poor asthma control occurred with similar frequency in the placebo and esomeprazole groups (2.3 and 2.5 events per person-year, respectively; P=0.66). There was no treatment effect with respect to individual components of the episodes of poor asthma control or with respect to secondary outcomes, including pulmonary function, airway reactivity, asthma control, symptom scores, nocturnal awakening, or quality of life. The presence of gastroesophageal reflux, which was documented by pH monitoring in 40% of participants with minimal or no symptoms, did not identify a subgroup of patients that benefited from treatment with proton-pump inhibitors. There were fewer serious adverse events among patients receiving esomeprazole than among those receiving placebo (11 vs. 17). CONCLUSIONS Despite a high prevalence of asymptomatic gastroesophageal reflux among patients with poorly controlled asthma, treatment with proton-pump inhibitors does not improve asthma control. Asymptomatic gastroesophageal reflux is not a likely cause of poorly controlled asthma. (ClinicalTrials.gov number, NCT00069823.)

Tiotropium Respimat inhaler and the risk of death in COPD.

BACKGROUND Tiotropium delivered at a dose of 5 μg with the Respimat inhaler showed efficacy similar to that of 18 μg of tiotropium delivered with the HandiHaler inhalation device in placebo-controlled trials involving patients with chronic obstructive pulmonary disease (COPD). Although tiotropium HandiHaler was associated with reduced mortality, as compared with placebo, more deaths were reported with tiotropium Respimat than with placebo. METHODS In this randomized, double-blind, parallel-group trial involving 17,135 patients with COPD, we evaluated the safety and efficacy of tiotropium Respimat at a once-daily dose of 2.5 μg or 5 μg, as compared with tiotropium HandiHaler at a once-daily dose of 18 μg. Primary end points were the risk of death (noninferiority study, Respimat at a dose of 5 μg or 2.5 μg vs. HandiHaler) and the risk of the first COPD exacerbation (superiority study, Respimat at a dose of 5 μg vs. HandiHaler). We also assessed cardiovascular safety, including safety in patients with stable cardiac disease. RESULTS During a mean follow-up of 2.3 years, Respimat was noninferior to HandiHaler with respect to the risk of death (Respimat at a dose of 5 μg vs. HandiHaler: hazard ratio, 0.96; 95% confidence interval [CI], 0.84 to 1.09; Respimat at a dose of 2.5 μg vs. HandiHaler: hazard ratio, 1.00; 95% CI, 0.87 to 1.14) and not superior to HandiHaler with respect to the risk of the first exacerbation (Respimat at a dose of 5 μg vs. HandiHaler: hazard ratio, 0.98; 95% CI, 0.93 to 1.03). Causes of death and incidences of major cardiovascular adverse events were similar in the three groups. CONCLUSIONS Tiotropium Respimat at a dose of 5 μg or 2.5 μg had a safety profile and exacerbation efficacy similar to those of tiotropium HandiHaler at a dose of 18 μg in patients with COPD. (Funded by Boehringer Ingelheim; TIOSPIR ClinicalTrials.gov number, NCT01126437.).

The minimal important difference of exercise tests in severe COPD

Our aim was to determine the minimal important difference (MID) for 6-min walk distance (6MWD) and maximal cycle exercise capacity (MCEC) in patients with severe chronic obstructive pulmonary disease (COPD). 1,218 patients enrolled in the National Emphysema Treatment Trial completed exercise tests before and after 4–6 weeks of pre-trial rehabilitation, and 6 months after randomisation to surgery or medical care. The St Georges Respiratory Questionnaire (domain and total scores) and University of California San Diego Shortness of Breath Questionnaire (total score) served as anchors for anchor-based MID estimates. In order to calculate distribution-based estimates, we used the standard error of measurement, Cohens effect size and the empirical rule effect size. Anchor-based estimates for the 6MWD were 18.9 m (95% CI 18.1–20.1 m), 24.2 m (95% CI 23.4–25.4 m), 24.6 m (95% CI 23.4–25.7 m) and 26.4 m (95% CI 25.4–27.4 m), which were similar to distribution-based MID estimates of 25.7, 26.8 and 30.6 m. For MCEC, anchor-based estimates for the MID were 2.2 W (95% CI 2.0–2.4 W), 3.2 W (95% CI 3.0–3.4 W), 3.2 W (95% CI 3.0–3.4 W) and 3.3 W (95% CI 3.0–3.5 W), while distribution-based estimates were 5.3 and 5.5 W. We suggest a MID of 26±2 m for 6MWD and 4±1 W for MCEC for patients with severe COPD.