Kathryn Rice

Prevention of Exacerbations of Chronic Obstructive Pulmonary Disease with Tiotropium, a Once-Daily Inhaled Anticholinergic Bronchodilator: A Randomized Trial

Context Tiotropium, a new once-daily inhaled anticholinergic bronchodilator, has been shown to improve lung function in patients with chronic obstructive pulmonary disease (COPD). Previous studies have suggested that it may also decrease the frequency of exacerbations and hospitalizations in these patients. Contribution This randomized, parallel-group, double-blind, placebo-controlled study in patients with moderate to severe COPD showed a small but statistically significant decrease in the exacerbation rate during the 6-month study period. Cautions The study period was relatively short, and the beneficial effects were modest. The Editors Exacerbations of chronic obstructive pulmonary disease (COPD) can lead to costly and clinically significant consequences. Proven treatments for exacerbations are only modestly effective (1, 2). Recovery from even mild exacerbations may be protracted (3). Frequent exacerbations are associated with impaired quality of life and a more rapid decline in lung function over time (4, 5). Patients with severe exacerbations commonly seek care in emergency departments, and many of these patients are hospitalized. In 2000, COPD was responsible for 1.5 million emergency department visits and 726000 hospitalizations in the United States (6). Economic analyses suggest that hospitalization alone consumes up to 70% of all medical expenses for patients with COPD (7, 8). Interventions that reduce the frequency or severity of exacerbations are a highly desirable but poorly met medical need. An expert panel convened by the National Heart, Lung, and Blood Institute assigned a high priority to clinical research that might improve the management of COPD exacerbations (9). Tiotropium is a newly developed, once-daily inhaled anticholinergic bronchodilator. Because of its very slow dissociation from muscarinic M3 receptors, 1 inhaled dose produces sustained bronchodilation for at least 24 hours (10). In controlled clinical trials, compared with placebo or the short-acting anticholinergic bronchodilator ipratropium, tiotropium improved lung function, dyspnea, and health-related quality of life in patients with COPD (11, 12). An analysis of adverse event reports submitted during those studies suggested that tiotropium might also reduce exacerbation and COPD-related hospitalization rates. Therefore, we designed a clinical trial to prospectively test the hypothesis that tiotropium reduces exacerbations and hospitalizations due to COPD. Methods Study Design Our study was a parallel-group, randomized, double-blind, placebo-controlled trial in patients with moderate to severe COPD conducted at 26 Veterans Affairs medical centers in the United States. The sole intervention was tiotropium given by inhalation once daily. The principal outcomes were the percentage of patients experiencing at least 1 exacerbation and the percentage of patients with at least 1 hospitalization due to a COPD exacerbation during a 6-month treatment period. The protocol is consistent with the principles of Helsinki. The institutional review boards of participating medical centers approved the study. All trial participants provided written informed consent. Patients All men and women receiving medical care at participating Veterans Affairs medical centers were potential study participants. We enrolled enough participants to ensure a minimum of 1800 randomly assigned patients. Eligibility criteria included an age of 40 years or older, a cigarette smoking history of 10 pack-years or more, a clinical diagnosis of COPD, and an FEV1 of 60% predicted or less and 70% or less of the FVC. Exclusion criteria were a clinical diagnosis of asthma, a myocardial infarction within the previous 6 months, a serious cardiac arrhythmia or hospitalization for heart failure within the previous year, known moderate to severe renal impairment, moderate to severe symptomatic prostatic hypertrophy or bladder-neck obstruction, narrow-angle glaucoma, current radiation or chemotherapy for a malignant condition, or inability to give informed consent. We also excluded patients who took systemic corticosteroids at unstable doses, or in regular daily doses of 20 mg or more of prednisone (or equivalent), or who had not fully recovered from an exacerbation for at least 30 days before the first study visit. We gathered baseline data on respiratory disease and other relevant medical history by questionnaire. Procedures We allocated eligible patients in equal numbers to receive tiotropium or placebo according to a centrally generated blocked randomization list. We generated a single randomization and assigned blocks to centers. We provided randomly assigned patients with training and detailed instructions on the use of the dry powder inhalation device (HandiHaler, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany) (13). Blinding of supplies was performed at Boehringer Ingelheim before distribution to investigational sites. The double-blind remained in place until all patients were clinically complete or until a serious adverse event required unblinding. Each morning during the trial, patients inhaled 1 capsule of tiotropium (18 g) or 1 identical placebo capsule. Participants otherwise received usual medical care, except that they could not take any open-label anticholinergic bronchodilator. They continued taking all other respiratory medications (including inhaled corticosteroids and long-acting -agonists), and primary providers were allowed to prescribe additional medications according to medical need. Primary providers also prescribed antibiotics and systemic steroid prescriptions for exacerbations without restrictions. For purposes of recall, patients kept a daily diary throughout the treatment period, recording information about specific respiratory symptoms, medications taken for exacerbations, clinic visits, and hospitalizations. We collected information about exacerbations and health care utilization by interviews when patients made site visits at 3 and 6 months and by telephone calls at 1-month intervals between visits. We assessed study drug adherence by query and by counting returned capsules. Participants performed spirometry before and 90 minutes after inhalation of study drug at baseline and again at the 3-month and 6-month visits. We encouraged patients to complete study visits and to provide all requested medical information even if they prematurely discontinued the study drug therapy. However, patients who discontinued the study drug therapy did not have 90-minute postinhalation spirometry testing at subsequent study visits. All open-label bronchodilators and the study drug were withheld overnight before spirometry. Study sites performed spirometry by using a common predictive nomogram with equipment and methods that conformed to American Thoracic Society recommendations (14, 15). Objectives We aimed to determine whether tiotropium decreased COPD exacerbations and hospitalizations due to exacerbations. Outcome Measures The coprimary outcomes were the percentage of patients with a COPD exacerbation and the percentage of patients with a hospitalization due to COPD exacerbation. We defined an exacerbation as a complex of respiratory symptoms (increase or new-onset) of more than 1 of the following: cough, sputum, wheezing, dyspnea, or chest tightness with a duration of at least 3 days requiring treatment with antibiotics or systemic steroids, hospitalization, or both. The study team at each site requested discharge summaries for all hospitalizations, wherever they occurred. We identified hospitalizations due to COPD exacerbations from events on case report forms that met the protocol definition of an exacerbation and where review of discharge summaries and other available medical records indicated that the event resulted in a hospitalization. We also considered an event to be a hospitalization if a patient was held and treated for an acute respiratory condition in an urgent care department or in an observation unit for longer than 24 hours. Admissions to nursing homes or other extended care facilities were not considered hospitalizations. Secondary outcomes included time to first COPD exacerbation and time to first hospitalization due to COPD exacerbation, the frequencies of exacerbations and of exacerbation-related health care utilization (hospitalizations, hospitalization days, unscheduled clinic visits, antibiotic treatment days, and systemic corticosteroid treatment days), the frequencies of all-cause hospitalizations and hospitalization days, and results of spirometry. Statistical Analysis We analyzed the data by using a modified intention-to-treat principle. Therefore, we included all available data for the patients with any follow-up contact who took at least 1 capsule of study drug in the analysis up to their first event (for the time-to-event end points) or their withdrawal from the trial. For the time-to-event end points, we censored patients without an event at the end of their participation in the trial. Although we intended to follow all patients for the full 6 months, some patients were lost to follow-up. We handled missing data by using longitudinal data analysis methods (spirometry), analysis of observed data only (number of events), or analysis methods for censored data (time-to-event data). For the percentage of patients with an event, we considered that patients who discontinued the study drug therapy before having an event did not have an event. We analyzed the coprimary end points by using a CochranMantelHaenszel test with center as a stratum. We used a stepwise procedure to test the percentage of patients with an exacerbation and, if rejected, to test percentage of patients with a hospitalization due to COPD exacerbation, each at a 2-sided level of 0.05. Because of the prespecified closed testing procedure, no adjustment for multiplicity was required. We calculated that a sample size of 1800 patients would have 80% power to dete

Disease management program for chronic obstructive pulmonary disease: a randomized controlled trial.

RATIONALE The effect of disease management for chronic obstructive pulmonary disease (COPD) is not well established. OBJECTIVES To determine whether a simplified disease management program reduces hospital admissions and emergency department (ED) visits due to COPD. METHODS We performed a randomized, adjudicator-blinded, controlled, 1-year trial at five Veterans Affairs medical centers of 743 patients with severe COPD and one or more of the following during the previous year: hospital admission or ED visit for COPD, chronic home oxygen use, or course of systemic corticosteroids for COPD. Control group patients received usual care. Intervention group patients received a single 1- to 1.5-hour education session, an action plan for self-treatment of exacerbations, and monthly follow-up calls from a case manager. MEASUREMENTS AND MAIN RESULTS We determined the combined number of COPD-related hospitalizations and ED visits per patient. Secondary outcomes included hospitalizations and ED visits for all causes, respiratory medication use, mortality, and change in Saint Georges Respiratory Questionnaire. After 1 year, the mean cumulative frequency of COPD-related hospitalizations and ED visits was 0.82 per patient in usual care and 0.48 per patient in disease management (difference, 0.34; 95% confidence interval, 0.15-0.52; P < 0.001). Disease management reduced hospitalizations for cardiac or pulmonary conditions other than COPD by 49%, hospitalizations for all causes by 28%, and ED visits for all causes by 27% (P < 0.05 for all). CONCLUSIONS A relatively simple disease management program reduced hospitalizations and ED visits for COPD. Clinical trial registered with www.clinicaltrials.gov (NCT00126776).

Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine in adults 70 years of age and older previously vaccinated with 23-valent pneumococcal polysaccharide vaccine

BACKGROUND The currently recommended single dose of the 23-valent pneumococcal free polysaccharide vaccine (PPSV23) for adults 65 years of age and older does not provide extended protection into older age. This reflects a significant unmet medical need for alternative strategies to protect older adults against pneumococcal infection, which may be met by the 13-valent polysaccharide conjugate vaccine (PCV13). METHODS We performed a randomized, modified double-blind trial in 936 adults aged 70 years and older who had previously received PPSV23 at least 5 years before study entry and were now vaccinated with PCV13 or PPSV23. At 1 year after enrollment, all subjects received a follow-on dose of PCV13. Anti-pneumococcal opsonophagocytic activity (OPA) titers were measured before and at 1 month after each vaccination. RESULTS Following the enrollment vaccination, OPA titers were significantly greater in the PCV13 group compared to the PPSV23 group for 10 of the 12 serotypes common to both vaccines and to serotype 6A which is unique to PCV13. Responses were noninferior for the other 2 common serotypes. Responses to PCV13 given at 1 year were generally lower in the group that received PPSV23 at enrollment. CONCLUSION In adults aged 70 years and older previously vaccinated with PPSV23, PCV13 was significantly more immunogenic than PPSV23 for most of the common serotypes and for serotype 6A. The OPA responses after a follow-on dose of PCV13 one year later indicate that a prior dose of PPSV23, but not PCV13, diminishes the response to the subsequent administration of PCV13.

Aminophylline for acute exacerbations of chronic obstructive pulmonary disease. A controlled trial

STUDY OBJECTIVE To determine the efficacy of intravenous aminophylline in the treatment of patients hospitalized for exacerbation of chronic obstructive pulmonary disease. DESIGN Randomized, double-blind, placebo-controlled trial during the first 72 hours of hospitalization. PATIENTS Thirty patients admitted from the emergency room or walk-in clinic with the primary diagnosis of an exacerbation of chronic obstructive pulmonary disease. Twenty-eight patients completed the study; 2 patients, 1 receiving placebo and 1 receiving aminophylline, were removed from the study because of respiratory failure requiring mechanical ventilation. INTERVENTIONS PATIENTS received either intravenous aminophylline or placebo, in addition to nebulized, inhaled 0.3 mL of a 5% solution every 6 hours; methylprednisolone, 0.5 mg/kg body weight every 6 hours intravenously; ampicillin, 500 mg orally every 6 hours (tetracycline or trimethoprim-sulfamethoxazole were substituted in penicillin-allergic patients); and supplemental oxygen as needed. Aminophylline infusion rates were adjusted by an unblinded investigator to achieve theophylline levels of 72 to 83 mumol/L. Changes were also made in placebo infusion rates to maintain the double-blind design. MEASUREMENTS AND MAIN RESULTS The forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) before and after metaproterenol inhalation were measured twice daily by a blinded investigator, who also administered a verbal dyspnea index with a scale of 1 to 10 and questioned patients regarding possible side effects of treatment (tremor, palpitations, nausea, or vomiting). Arterial blood gas measurements at 72 hours were compared with those obtained on admission. Significant improvements in FEV1 and FVC measured before and after metaproterenol treatment and in dyspnea occurred over time in both treatment groups (p less than 0.05 for all measurements). However, there were no significant differences between the placebo and aminophylline groups in any of the spirometric measurements or the dyspnea indices (p greater than 0.5 in all five analyses). The mean increases (+/- SE) in Po2 of 1.9 (+/- 0.5) kPa with placebo and 1.7 (+/- 0.7) kPa with aminophylline and the mean decreases in PCO2 of 0.5 (+/- 0.4) kPa with placebo and 1.2 (+/- 0.4) kPa with aminophylline were not significantly different (p greater than 0.6 for PO2, p greater than 0.2 for PCO2).(ABSTRACT TRUNCATED AT 400 WORDS)

Genome-wide association study of smoking behaviours in patients with COPD

Background Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease (COPD) and COPD severity. Previous genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with the number of cigarettes smoked per day (CPD) and a dopamine beta-hydroxylase (DBH) locus associated with smoking cessation in multiple populations. Objective To identify SNPs associated with lifetime average and current CPD, age at smoking initiation, and smoking cessation in patients with COPD. Methods GWAS were conducted in four independent cohorts encompassing 3441 ever-smoking patients with COPD (Global Initiative for Obstructive Lung Disease stage II or higher). Untyped SNPs were imputed using the HapMap (phase II) panel. Results from all cohorts were meta-analysed. Results Several SNPs near the HLA region on chromosome 6p21 and in an intergenic region on chromosome 2q21 showed associations with age at smoking initiation, both with the lowest p=2×10−7. No SNPs were associated with lifetime average CPD, current CPD or smoking cessation with p<10−6. Nominally significant associations with candidate SNPs within cholinergic receptors, nicotinic, alpha 3/5 (CHRNA3/CHRNA5; eg, p=0.00011 for SNP rs1051730) and cytochrome P450, family 2, subfamily A, polypeptide 6 (CYP2A6; eg, p=2.78×10−5 for a non-synonymous SNP rs1801272) regions were observed for lifetime average CPD, however only CYP2A6 showed evidence of significant association with current CPD. A candidate SNP (rs3025343) in DBH was significantly (p=0.015) associated with smoking cessation. Conclusion The authors identified two candidate regions associated with age at smoking initiation in patients with COPD. Associations of CHRNA3/CHRNA5 and CYP2A6 loci with CPD and DBH with smoking cessation are also likely of importance in the smoking behaviours of patients with COPD.

Efficacy trial of live, cold-adapted and inactivated influenza virus vaccines in older adults with chronic obstructive pulmonary disease: a VA cooperative study

We assessed whether trivalent live, cold-adapted influenza virus (CAIV-T) vaccine provides added protection when co-administered with trivalent inactivated influenza virus vaccine (TVV) in patients with chronic obstructive pulmonary disease (COPD). Subjects (N=2215) were randomly assigned to receive either TVV intramuscularly (IM) and CAIV-T intranasally (TC), or TVV and placebo (TP). The vaccines were well-tolerated. Efficacy of TC compared to TP was not statistically significant and was 0.16 for any influenza virus strain (95% confidence limit (CL): -0.22, 0.43), 0.26 for A (H3N2) virus (95% CL: -0.17, 0.53), and -0.05 for type B virus (95% CL: -1.13, 0.48). However, there was a possible advantage for TC over TP in reducing respiratory consequences of an influenza season measured by pulmonary function and symptoms at end of study.

EFFECTS OF CHRONIC ADMINISTRATION OF CODEINE AND PROMETHAZINE ON BREATHLESSNESS AND EXERCISE TOLERANCE IN PATIENTS WITH CHRONIC AIRFLOW OBSTRUCTION

It has been reported that short-term treatment with relatively high doses of opiates or promethazine causes improvements in dyspnoea and exercise tolerance in patients with chronic airflow obstruction (CAO). This study was designed to determine whether initial benefits were sustained during chronic administration of codeine or promethazine and to compare the two drugs in terms of their efficacy and possible mechanisms of action. Eleven patients with stable CAO were entered into a double-blind, randomized cross-over trial in which codeine (30 mg four times daily) or promethazine (25 mg four times daily) were orally administered for 1-month periods. Treatment effects were assessed by spirometry, arterial blood gases, 12-minute walk distance and subjective dyspnoea ratings. A statistically significant increase from the baseline in mean arterial PCO2 at at 24 hours (P less than 0.01) and at 1 month (P less than 0.05) occurred with codeine administration. There was no significant change from baseline for any other measurement with either drug, and no differences were detected between the two treatment arms. Four of the eleven patients did not complete the study; three of the four experienced worsening of their CAO requiring hospitalization (two while receiving codeine, one while receiving promethazine). We conclude that chronic treatment with either codeine or promethazine provides uncertain benefits to patients with CAO which may not outweigh potential risks.

Exhaled nitric oxide, systemic inflammation, and the spirometric response to inhaled fluticasone propionate in severe chronic obstructive pulmonary disease: A prospective study

Background: A subset of patients with chronic obstructive pulmonary disease (COPD) may respond more favorably to inhaled corticosteroids (ICS), but no simple method is currently utilized to predict the presence or absence of ICS responses in patients with COPD. We evaluated the ability of exhaled nitric oxide (FENO) and serum inflammatory markers (C-reactive protein [CRP], interleukin-6 [IL-6], and interleukin-8 [IL-8]) to independently predict spirometric responses to ICS in patients with COPD. Methods: Among 60 ex-smokers with severe COPD (mean FEV1 1.07 L, 36% of predicted), we conducted a single-arm, open-label study. Participants spent four weeks free of any ICS, followed by four weeks of ICS use (fluticasone propionate 500 mcg twice daily). FENO, CRP, IL-6, IL-8, and pre-bronchodilator spirometry were measured immediately before and after the four weeks of ICS use. Results: Baseline FENO, CRP, IL-6, and IL-8 showed no correlations to FEV1 responses to ICS. ICS responders (increase in FEV1 ≥ 200 mL after four weeks of ICS) did have significantly higher baseline FENO levels compared with non-responders (46.5 parts per billion [ppb] vs. 25 ppb, p = 0.028). The receiver operating characteristic curve for FENO to discriminate responders from non-responders had an area under curve of 0.72. Baseline serum inflammatory markers did not differ between responders and non-responders. Conclusion: In ex-smokers with severe COPD, a measure of local pulmonary inflammation, FENO, may be more closely associated with FEV1 responses to four weeks of ICS than are standard markers of systemic inflammation, serum CRP, IL-6, and IL-8

Preoperative pulmonary function and mortality after cardiac surgery

BACKGROUND The aim of the study was to examine the relationship between preoperative pulmonary function and outcomes after cardiac surgery. METHODS We performed preoperative pulmonary function tests (PFTs) in 1,169 patients undergoing cardiac surgery at the Minneapolis Veterans Affairs Medical Center. Airway obstruction was defined as forced expiratory volume in 1 minute (FEV(1)) to forced vital capacity ratio <0.7. RESULTS Of the 1,169 patients, 483 (41%) had a prior history of chronic obstructive pulmonary disease (COPD). However, 178 patients with a history of COPD had no airway obstruction on PFT. Conversely, 186 patients without a COPD history had airway obstruction on PFT. Thus, PFT results helped reclassify the COPD status of 364 patients (31%). Operative mortality was 2% in patients with no or mild airway obstruction versus 6.7% in those with moderate or severe obstruction (ie, FEV(1) to forced vital capacity ratio <0.7 and FEV(1) <80% predicted). Postoperative mortality was higher (odds ratio 3.2, 95% CI 1.6-6.2, P = .001) in patients with moderate or severe airway obstruction and in patients with diffusing capacity of the lung for carbon monoxide <50% of predicted (odds ratio 4.9, 95% CI 2.3-10.8, P = .0001). Notably, mortality risk was 10x higher (95% CI 3.4-27.2, P = .0001) in patients with moderate or severe airway obstruction and diffusing capacity of the lung for carbon monoxide <50% of predicted. CONCLUSIONS These data show that PFT before cardiac surgery reclassifies the COPD status of a substantial number of patients and provides important prognostic information that the current risk estimate models do not capture.

Definition of a COPD self-management intervention: International Expert Group consensus

There is an urgent need for consensus on what defines a chronic obstructive pulmonary disease (COPD) self-management intervention. We aimed to obtain consensus regarding the conceptual definition of a COPD self-management intervention by engaging an international panel of COPD self-management experts using Delphi technique features and an additional group meeting. In each consensus round the experts were asked to provide feedback on the proposed definition and to score their level of agreement (1=totally disagree; 5=totally agree). The information provided was used to modify the definition for the next consensus round. Thematic analysis was used for free text responses and descriptive statistics were used for agreement scores. In total, 28 experts participated. The consensus round response rate varied randomly over the five rounds (ranging from 48% (n=13) to 85% (n=23)), and mean definition agreement scores increased from 3.8 (round 1) to 4.8 (round 5) with an increasing percentage of experts allocating the highest score of 5 (round 1: 14% (n=3); round 5: 83% (n=19)). In this study we reached consensus regarding a conceptual definition of what should be a COPD self-management intervention, clarifying the requisites for such an intervention. Operationalisation of this conceptual definition in the near future will be an essential next step. Consensus of a conceptual definition of what should be a COPD self-management intervention with its requisites http://ow.ly/Zfr0F