Timothy J. Wilt, MD, MPH; Dennis Niewoehner, MD; Roderick MacDonald, MS; Robert L. Kane, MD
Disclaimer: The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the AHRQ or the U.S. Department of Health and Human Services.
Acknowledgment: The authors thank Indy Rutks, who assisted in the literature search and creation of some figures.
Grant Support: Prepared by the Minnesota AHRQ Evidence-based Practice Center, Minneapolis, Minnesota, under AHRQ contract no. 290-02-0009 and a contract with the American College of Physicians.
Potential Financial Conflicts of Interest: Consultancies: D. Niewoehner (Boehringer Ingelheim, AstraZeneca, GlaxoSmithKline, Sanofi Aventis, Schering-Plough, Adams Respiratory Therapeutics). Honoraria: D. Niewoehner (Pfizer Inc., Boehringer Ingelheim). Grants received: D. Niewoehner (Boehringer Ingelheim, GlaxoSmithKline).
Requests for Single Reprints: Timothy J. Wilt, MD, MPH, Veterans Affairs Medical Center (111-0), Minneapolis, MN 55417; e-mail, email@example.com.
Current Author Addresses: Dr. Wilt and Mr. MacDonald: University of Minnesota School of Medicine, Center for Chronic Disease Outcomes Research (111-0), Veterans Affairs Medical Center, 1 Veterans Drive, Minneapolis, MN 55417.
Dr. Niewoehner: University of Minnesota School of Medicine, Pulmonary Section (111A), Veterans Affairs Medical Center, 1 Veterans Drive, Minneapolis, MN 55417.
Dr. Kane: Clinical Outcomes Research Center, School of Public Health, Health Policy and Management, University of Minnesota, Minneapolis, MN 55455.
Wilt T., Niewoehner D., MacDonald R., Kane R.; Management of Stable Chronic Obstructive Pulmonary Disease: A Systematic Review for a Clinical Practice Guideline. Ann Intern Med. 2007;147:639-653. doi: 10.7326/0003-4819-147-9-200711060-00009
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Published: Ann Intern Med. 2007;147(9):639-653.
Chronic obstructive pulmonary disease (COPD) is a common and disabling condition in adults. Information about therapeutic effectiveness and adverse effects of common treatment options and how clinical and spirometric characteristics affect outcomes is not well known but is important for clinicians caring for patients with stable COPD.
To evaluate the effectiveness of COPD management strategies.
English-language publications in MEDLINE and the Cochrane Library through March 2007.
Randomized, controlled trials (RCTs) and previous systematic reviews of inhaled therapies, pulmonary rehabilitation, disease management, and supplemental oxygen in adults with COPD.
Participant, study, and intervention characteristics; exacerbations; deaths; respiratory health status; exercise capacity; hospitalizations; and adverse effects.
Eight meta-analyses and 42 RCTs examined inhaled therapies: short-acting anticholinergics (nÂ = 7), long-acting anticholinergics (nÂ = 10), long-acting Î²2-agonists (nÂ = 22), corticosteroids (nÂ = 14), dual D2 dopamine receptorâ€“Î²2-agonist (nÂ = 3), or short-acting Î²2-agonist plus ipratropium (nÂ = 3). Evidence for nonpharmacologic therapies included 3 reviews of 39 RCTs plus 6 additional RCTs of pulmonary rehabilitation, 2 reviews of 13 RCTs plus 2 additional RCTs of disease management, and 8 RCTs of oxygen. Overall, long-acting inhaled therapies, used alone or in combination, reduced exacerbations more than placebo by 13% to 25% and had similar effectiveness to each other. Average improvements in health status scores were less than what is considered to be clinically noticeable. Inhaled monotherapy did not reduce mortality rates. Inhaled corticosteroids plus long-acting Î²2-agonists reduced deaths in relative terms compared with placebo (relative risk, 0.82 [95% CI, 0.69 to 0.98]) and inhaled corticosteroids alone (relative risk, 0.79 [CI, 0.67 to 0.94]) but not compared with long-acting Î²2-agonists alone (relative risk, 0.82 [CI, 0.52 to 1.28]). Absolute reductions were 1% or less and were not statistically significant. Pulmonary rehabilitation improved health status and dyspnea but not walking distance. Neither disease management nor ambulatory oxygen improved measured outcomes. Supplemental oxygen reduced mortality rates among symptomatic patients with resting hypoxia (relative risk, 0.61 [CI, 0.46 to 0.82]). Insufficient evidence supports using spirometry to guide therapy.
Articles were limited to those in the English language. Treatment adherence, adverse effects, and effectiveness may differ among clinical settings. Short-acting inhalers for â€œrescue therapyâ€ were not evaluated.
Long-acting inhaled therapies, supplemental oxygen, and pulmonary rehabilitation are beneficial in adults who have bothersome respiratory symptoms, especially dyspnea, and FEV1 less than 60% predicted.
In the United States, more than 5% of adults have symptomatic chronic obstructive pulmonary disease (COPD), which is a leading cause of morbidity and mortality (1, 2). Treatment options include inhaled pharmacologic therapy with short- or long-acting bronchodilators or corticosteroids, pulmonary rehabilitation, disease management, and supplemental oxygen (3). Long-acting inhaled bronchodilators and pulmonary rehabilitation have been recommended for patients with spirometrically detected obstruction, even without symptoms (3). Addition of inhaled corticosteroids to long-acting bronchodilators (combination therapy) has been recommended for individuals with repeated exacerbations and an FEV1 less than 50% predicted. Information about therapeutic effectiveness and adverse effects of common treatment options and how clinical and spirometric characteristics affect outcomes is not well known but is important for clinicians caring for patients with stable COPD.
This review updates a report prepared for the Agency for Healthcare Research and Quality (AHRQ) and serves as the background paper for an American College of Physician's Clinical Practice Guideline (4). It addresses the following questions: Which inhaled therapies are effective for treatment and maintenance of stable COPD? When should clinicians consider pulmonary rehabilitation and disease management? When should clinicians prescribe oxygen therapy? Should clinicians base treatment decisions on spirometric results, symptoms, or both?
Detailed information on the use of spirometry for diagnosis and case finding is available in the original AHRQ report at http://www.ahrq.gov/clinic/tp/spirotp.htm. Spirometry for case finding and management would be useful if it identified individuals who were not clinically detected as candidates for COPD treatments, excluded individuals with false-positive clinical presentations for COPD, or independently identified thresholds to guide initiation or modification of therapies. Our previous report identified insufficient evidence to support these conditions.
For our previous report, we searched PubMed and the Cochrane Library for articles published in English from 1966 through May 2005. The current review extends the search related to COPD therapies through March 2007 by using search terms used in a 2003 review by Sin and colleagues (5) to identify randomized, controlled trials (RCTs), controlled clinical trials, meta-analyses, and reviews published since the completion of their search in 2002. To supplement our search, we examined the Cochrane Database of Systematic Reviews of Effectiveness, examined bibliographies of published articles, and contacted experts. We categorized interventions as 1) inhaled medications (β2-agonists, anticholinergics, combination β2-agonists and anticholinergics, inhaled corticosteroids, and combination inhaled corticosteroids and long-acting β2-agonists or anticholinergics), 2) pulmonary rehabilitation, 3) disease management programs, and 4) oxygen therapy.
Two reviewers used standardized data abstraction sheets to examine titles and abstracts of newly identified references. If both reviewers agreed on eligibility, we included the article. Disagreement among reviewers, although rare, was resolved by discussion, with final decision by the lead author. Trials were eligible if they were randomized; involved persons with COPD that was defined clinically or by spirometry; and measured clinical outcomes, including exacerbations, standardized respiratory health status measures, hospitalizations, and deaths. Studies reporting only spirometry outcomes were ineligible. Inhaled therapy trials had to include 50 or more participants per treatment group and at least 3 months of follow-up. Trials of pulmonary rehabilitation programs had to include at least 6 weeks of follow-up and a usual care comparison group. We excluded studies that compared different types of pulmonary rehabilitation, and we included systematic reviews and meta-analyses of COPD therapies.
Two individuals extracted data onto standardized forms. The lead author resolved any disagreements. Main outcomes for all interventions were the percentage of participants experiencing at least 1 exacerbation, mean change in respiratory health status, hospitalization, and death. Respiratory health status was assessed by the validated St. George Respiratory Questionnaire (SGRQ) or the Chronic Respiratory Disease Questionnaire (CRDQ). A 4-unit reduction (out of 100) on the SGRQ and a 0.5-unit increase per question on the 7-question CRDQ are defined as clinically noticeable improvements (6). For pulmonary rehabilitation, we collected information on the 6-minute walk test and defined a minimally clinically significant effect size as 53 meters or more.
We collected data on adverse effects of long-acting inhaled therapies (including specifically described adverse effects, “serious adverse effects,” treatment adherence, study withdrawals, and withdrawals due to adverse effects) from trials that lasted at least 1 year and from systematic reviews that specifically addressed adverse effects. We assessed whether these studies used placebo or active control run-in periods, as well as the number and reasons for exclusion of potentially eligible patients from randomization during the run-in period.
We used the methods of Schulz and colleagues (7) to assess the quality of randomized trials on the basis of allocation concealment. We assessed blinding, intention-to-treat analysis, length of follow-up, withdrawals or loss to follow-up, and funding source. We rated the quality of systematic reviews or meta-analysis according to the Strength of Recommendation Taxonomy (8). An RCT was considered high quality if it had allocation concealment, blinding (if possible), intention-to-treat analysis, adequate size, and adequate follow-up (>80%). Systematic reviews or meta-analysis with high-quality studies and consistent findings are indicated as good-quality, patient-oriented evidence.
Intervention effectiveness was described according to baseline respiratory symptom status, spirometrically defined level of airflow obstruction, acute change in spirometry, or spirometric change over time (inhaled medications and use of spirometry to guide therapy). The magnitude of effect across interventions (inhaled therapies and oxygen) was based on relative risks and absolute risk differences, as well as comparison with previously determined, minimally important clinical differences in respiratory health status and exercise capacity. Study results were combined, if appropriate, to produce pooled estimates. We calculated relative risks and 95% CIs for categorical variables and weighted mean differences and 95% CIs for continuous variables. We conducted analyses by using a DerSimonian–Laird random-effects model in Review Manager software, version 4.2 (The Cochrane Collaboration, Oxford, United Kingdom) (9). We assessed heterogeneity by using a chi-square test and the I2 test. An I2statistic of 50 or greater indicates substantial heterogeneity (10). If heterogeneity existed, we conducted sensitivity analyses to explore potential causes of heterogeneity.
This project was funded by the AHRQ, U.S. Department of Health and Human Services. The updated synthesis was conducted in collaboration with the American College of Physicians' Clinical Efficacy Assessment Subcommittee. Panel members assisted in the formulation of questions and reviewing drafts of this report. The funding source had no role in the design, conduct, or reporting of the study or in the decision to submit the manuscript for publication.
Figure 1 shows that 42 RCTs involving short- or long-acting inhaled monotherapy or combination therapy (ipratropium [11–17], tiotropium [14, 15, 18–25]), long-acting β2-agonists (11, 13, 14, 17, 18, 21, 26–41), corticosteroids (28, 29, 32, 33, 38–47), dual D2 dopamine receptor–β2-agonist (sibenadet) (30, 48, 49), short-acting β2-agonists, and ipratropium (50–52) versus placebo or active control and 8 meta-analyses of RCTs (5, 53–59) were included for assessment of COPD inhaled therapies. We have identified 10 RCTs and 5 systematic reviews since our AHRQ report. Our updated search yielded an additional 16 RCTs and 2 systematic reviews of nonpharmacologic treatments. Three systematic reviews of 39 unique RCTs and 6 additional RCTs evaluated pulmonary rehabilitation (6 RCTs and 1 systematic review were added for our review) (5, 60–90). Two systematic reviews of 13 unique RCTs and 2 additional trials evaluating disease management, education, and follow-up were eligible (2 RCTs and 1 systematic review were added for our review) (5, 91–106). Supplemental oxygen therapy was not addressed in our original report. We included 8 RCTs and 1 systematic review evaluating 7 of these 8 trials (5, 107–114).
RCT = randomized, controlled trial.
Appendix Table 1 and other systematic reviews (5, 60, 61, 91) describe the included randomized trials. We identified no study quality differences according to type of inhaled medication.
Appendix Table 1.
Concealment of treatment allocation for inhaled therapies was adequate in 17 studies (12, 22, 25, 26, 29–31, 36–40, 42, 44, 46, 47, 49). All trials were double-blind, and nearly all used intention-to-treat analyses. Several included only participants who were taking at least 1 dose or who had 1 valid postbaseline measurement (17, 23, 30, 32, 38, 42, 44, 48, 49) or excluded participants because of noneligibility after randomization or good practice or ethics violations by individual study sites (26, 39). All but 7 studies were funded by pharmaceutical companies. All trials had adequate participant follow-up (>80%). Six trials lasted 3 years or longer (12, 39, 42, 44, 45, 47).
Concealment of treatment allocation for trials of pulmonary rehabilitation and oxygen therapy was adequate in 1 and 4 studies, respectively (87, 107, 109, 111, 113). One disease management trial adequately randomly assigned practice centers but did not use individual randomization (106). Among nonpharmacologic trials, 7 used intention-to-treat analysis (86, 107–112). Five trials reported double-blinding (87, 89, 111, 112, 114), and 4 trials indicated blinded assessment of outcomes (85, 89, 107, 113). Four oxygen therapy trials lasted 2 years or longer (76–79).
Almost all COPD treatment trials involved participants who were prone to exacerbations, had previous diagnoses of COPD, had disabling respiratory symptoms, had mean FEV1 less than 50% predicted, and used inhaled therapies. Only 4 RCTs used population-based recruitment and enrolled participants similar to those likely to be identified by spirometric case finding of “at-risk” individuals (11, 42, 44, 46), although some trials provided additional analysis according to spirometric status.
The Table summarizes the strength of the evidence for each question addressed in our review.
Monotherapies with inhaled long acting β2-agonists, a long-acting anticholinergic, or corticosteroids were of similar effectiveness and were superior to placebo or short-acting anticholinergics in reducing exacerbations (Figures 2 and 3). Compared with placebo, inhaled corticosteroids, long-acting bronchodilators (tiotropium, β2-agonists), or both reduced the relative risk for having at least 1 exacerbation by 13% to 17% and the absolute risk by 4% to 6%. Ipratropium, a short-acting anticholinergic, was not superior to placebo. In active comparator studies, long-acting β2-agonists were of similar effectiveness to corticosteroids or the short- or long-acting anticholinergics, ipratropium, or tiotropium.
LABA = long-acting β2-agonist; RR = relative risk.
LABA = long-acting β2-agonist; NA = not applicable; RR = relative risk; SABA = short-acting β2-agonist.
The incremental effect of combination therapy with inhaled corticosteroids and long-acting β2-agonists versus monotherapy using these agents was of borderline statistical significance, as assessed in 6 multigroup trials lasting 6 to 36 months (mean baseline FEV1 <50%) (Figures 2 and 3). The pooled absolute risk differences in the percentage of participants having at least 1 exacerbation for long-acting β2-agonists, corticosteroids, and combination therapy were −4% [95% CI, −8% to −1%], −5% [CI, −11% to 1%], and −6% [CI, −12% to −1%], respectively, compared with placebo (28, 29, 34, 41). Combination therapy did not reduce the value compared with monotherapy with either inhaled corticosteroids or long-acting β2-agonists (relative risk, 0.88 [CI, 0.75 to 1.17] vs. β2-agonists and 0.96 [CI, 0.85 to 1.08] vs. inhaled corticosteroids) (28, 29, 34, 41). A large 3-year RCT (TORCH [Towards a Revolution in COPD Health] ) of combination long-acting β2-agonist plus inhaled corticosteroid (fluticasone, 500 µg twice daily) versus placebo, long-acting β2-agonist, or inhaled corticosteroid monotherapy evaluated the annual rate of moderate to severe exacerbations in symptomatic adults with severe airflow obstruction. Pooling these results was not possible because the study (39) reported only annual rates of exacerbations (rather than proportions). The study investigators observed a statistically significant relative risk reduction of nearly identical magnitude to our pooled findings (relative risk, 0.75 [CI, 0.69 to 0.81] vs. placebo; 0.88 [CI, 0.81 to 0.95] vs. β2-agonists; and 0.91 [CI, 0.84 to 0.99] vs. inhaled corticosteroids). However, another trial found no difference in the annual rate of moderate to severe exacerbations or time to first exacerbation (P = 0.15) regardless of baseline FEV1 among participants randomly assigned to continue combination therapy with salmeterol–fluticasone compared with those in whom fluticasone therapy (500 µg twice daily) was withdrawn (40).
One 3-group trial lasting for 1 year evaluated combination therapy with all 3 classes of inhalers. The proportion of participants who experienced an exacerbation did not differ among those receiving monotherapy with a long-acting anticholinergic (tiotropium) (62.8%), those receiving combination tiotropium plus a long-acting β2-agonist (salmeterol) (64.8%), or those receiving all 3 therapies (tiotropium plus corticosteroid plus a long-acting β2-agonist [salmeterol–fluticasone]) (60.0%) (25) (Figure 3). The combination of a short-acting β2-agonist (albuterol) plus ipratropium reduced exacerbations compared with albuterol alone (absolute risk difference, −6%) (50–52).
Twenty trials, including the largest (38), reported SGRQ or CRDQ outcomes, but published results often did not permit pooling. Except for 5 trials (11, 25, 28, 33, 36), the average improvement in health status because of monotherapy or combination therapy was not considered clinically significant (6) (Appendix Table 2). In secondary analyses of 2 trials of tiotropium (18, 19), the percentage of individuals achieving a clinically significant difference in the SGRQ was greater with tiotropium than with placebo (49% vs. 35%).
Appendix Table 2.
Few RCTs reported hospitalization results. When reported, reductions were not consistently observed and do not permit definitive conclusions on the relative effectiveness of inhaled therapies. Monotherapy with a long-acting β2-agonist and combination therapy of long-acting β2-agonists and corticosteroids reduced the relative annual rate of severe exacerbations requiring hospitalizations by 17% and 18%, respectively, versus placebo in the TORCH study (39). The 12% relative reduction with inhaled corticosteroids did not achieve statistical significance (rate ratio, 0.88 [CI, 0.74 to 1.03]). Combination therapy was not superior to β2-agonists (rate ratio, 1.02 [CI, 0.87 to 1.20]) or inhaled corticosteroids (rate ratio, 0.95 [CI, 0.82 to 1.12]) used as monotherapy. Combination therapy with tiotropium plus salmeterol–fluticasone (but not tiotropium plus salmeterol) reduced hospitalizations for acute COPD exacerbations (rate ratio, 0.53 [CI, 0.33 to 0.86]) and all-cause hospitalizations versus tiotropium alone (25). Three trials lasting 3 to 12 months of long-acting β2-agonist therapy in participants with a mean FEV1 less than 60% predicted demonstrated a 2% reduction (CI, −5% to 1%) compared with placebo that was not statistically significant (11, 18, 34). The Lung Health Study (LHS) I and II enrolled persons with mild to moderate airflow obstruction (mean FEV1, 75% and 64% predicted, respectively; trial duration, 5 years) (12, 43). The LHS I showed no statistically significant differences in hospitalizations per 100 person-years of exposure between ipratropium and placebo (12). In LHS II, inhaled corticosteroids resulted in a small and nonsignificant decrease in hospitalizations per 100 person-years of exposure for respiratory conditions (P = 0.07) and no difference in nonrespiratory hospitalizations (43). The proportion of participants requiring hospitalization for COPD was lower with tiotropium than with placebo (absolute risk difference, −2% [CI, −4% to −1%]) (18, 19, 22, 24) and with ipratropium (absolute risk difference, −4% [CI, −10% to 1%]) (mean FEV1 <60%; trial duration, 6 months to 1 year) (14).
Death was the primary end point in only 1 trial (39). Mortality rates did not statistically differ in any trial or in pooled analyses of monotherapies (Figure 4). In a retrospective individual-patient data meta-analysis published before the TORCH study (56), inhaled corticosteroids resulted in a 1% absolute reduction in all-cause mortality compared with placebo (hazard ratio, 0.75 [CI, 0.57 to 0.99]). The mortality rate was not reduced among participants with a baseline FEV1 of 60% predicted or more (hazard ratio, 0.90 [CI, 0.54 to 1.53]). Combination therapy with long-acting β2-agonists plus inhaled corticosteroids reduced the relative but not the absolute risk for death compared with placebo (relative risk, 0.82 [CI, 0.69 to 0.98]; absolute risk difference, −0.01 [CI, −0.03 to 0.01]) and inhaled corticosteroids (relative risk, 0.79 [CI, 0.67 to 0.94]; absolute risk difference, −0.01 [CI, −0.03 to 0.02]). Neither the relative nor the absolute risk for death improved with combination long-acting β2-agonists plus inhaled corticosteroids compared with long-acting β2-agonists (relative risk, 0.90 [CI, 0.76 to 1.08].
LABA = long-acting β2-agonist; LHS = Lung Health Study; RR = relative risk.
Appendix Table 3 shows withdrawals and adverse events with long-acting inhaled therapies compared with placebo. An additional active comparator study evaluated combining the long-acting anticholinergic tiotropium with the β2-agonists salmeterol or salmeterol–fluticasone versus tiotropium alone (25). All but the tiotropium combination study (25) used a run-in period before randomization of initially eligible participants. The duration (10 days to 3 months), interventions allowed or provided (placebo, study drug, nonstudy chronic COPD medications, or rescue therapies), and reasons for exclusion (adherence, adverse events, and additional eligibility criteria) varied across studies. The mean percentage of persons who were enrolled in the run-in period but were not subsequently randomly assigned was 23% and ranged from 10% to 29% in the 12 trials that reported this information (25, 28, 29, 35, 36, 39–43, 45, 47). In the 7 trials that reported reasons for exclusions, 19% were mainly due to adverse events, followed by inadequate adherence to run-in medications (28, 36, 39–42, 47). None of the trials adequately described how the cause, severity, or duration of an adverse event was assessed, with the exception of fractures. Inconsistencies in adverse events reporting limited quantitative synthesis.
Appendix Table 3.
“All study withdrawals” occurred less frequently among persons randomly assigned to tiotropium (21%) (19, 24), long-acting β2-agonists (33%) (28, 29, 35, 36, 39, 41), corticosteroids (31%) (28, 29, 35, 36, 39, 41), or combination long-acting β2-agonists plus corticosteroids (32%) compared with placebo (28% to 44%). All study withdrawals were less likely to occur with combination therapy than with long-acting β2-agonist monotherapy (32% vs. 37%; relative risk, 0.82 [CI, 0.71 to 0.96]) or corticosteroid monotherapy (32% vs. 37%; relative risk, 0.87 [CI, 0.80 to 0.94]) (28, 29, 39, 41). Fewer withdrawals occurred with the combination of all 3 classes of long-acting inhaled agents (anticholinergics, β2-agonists, and corticosteroids) versus long-acting anticholinergic monotherapy (relative risk, 0.54 [CI, 0.30 to 0.96]) (25). “Withdrawals due to adverse effects” were similar or lower with inhaled therapies than with placebo. About 50% of enrollees remained adherent to therapy as prescribed. Adverse events during follow-up were usually minor and were seldom more than with placebo. “Serious adverse events” did not statistically significantly differ with inhaled treatment used as monotherapy or in combination therapy versus placebo. “Serious adverse events” occurred in 10% of participants receiving inhaled corticosteroids as monotherapy or combination therapy in the TORCH trial compared with 6% of participants receiving placebo or long-acting β2-agonists (39). Compared with placebo, adverse events that were considered to be related to treatment were more common with tiotropium and corticosteroids but not with long-acting β2-agonists. The frequencies of serious adverse events did not differ between combination therapy and long-acting β2-agonists or corticosteroids used as monotherapy (28, 39, 40).
The most common specific adverse effects of tiotropium were dry mouth, occurring in 10.3% of participants (relative risk, 4.4 [CI, 2.2 to 8.8] vs. placebo) (19, 24), and urine retention (odds ratio, 2.5 [CI, 0.5 to 14] vs. placebo) (53). Respiratory infections and pneumonia were similar with long-acting β2-agonists and with placebo (28, 35, 36, 38). A meta-analysis of 20 RCTs assessed the cardiovascular effects of inhaled β2-agonists (primarily salmeterol and formoterol) in patients with asthma or COPD. β2-Agonists were associated with an increase in cardiovascular events compared with placebo (2.7% vs. 0.7%) (56). Of these events, 87% were due to sinus tachycardia. Major cardiovascular events were higher compared with placebo, although they did not statistically differ (relative risk, 1.66 [CI, 0.76 to 3.60]). Another pooled analysis concluded that respiratory deaths increased with long-acting β2-agonists and decreased with anticholinergics (59). However, their conclusions were based on very few events; were not verified in our review of the published primary literature; included findings from duplicate publications; and did not incorporate the TORCH study, which found no difference in deaths due to pulmonary causes between placebo and salmeterol (5% in each group) (39).
Three trials provided information about the risk for pneumonia with inhaled corticosteroid use lasting up to 3 years. Pooled analysis showed significant heterogeneity (P = 0.02; I2 = 74%), which disappeared (P = 0.56; I2 = 0%) when the smallest trial that enrolled younger patients with mild airflow obstruction was excluded. In 2 trials, inhaled corticosteroids were associated with an increased risk for pneumonia compared with placebo (relative risk, 1.55 [CI, 1.33 to 1.80]). Inhaled corticosteroids were associated with an increased frequency of oropharyngeal candidiasis (28, 29, 42, 43, 45), throat irritation (28, 29, 42, 45), and a moderate to severe degree of easy bruising (29, 42, 45). After 3 years, lumbar spine and femur bone mineral density were lower in the LHS II triamcinolone group (43), but not in a small subset evaluated in TORCH (39). Pooled results from 3 RCTs indicated that fracture incidence was similar for inhaled corticosteroids used alone or in combination with long-acting β2-agonists for up to 3 years versus placebo (pooled relative risk, 0.96 [CI, 0.55 to 1.68]) (39, 42, 45). In the trial evaluating all 3 classes of long-acting inhaled therapies, 47% of patients in the tiotropium plus placebo group discontinued study medications compared with 43% in the tiotropium plus salmeterol group and 26% in the tiotropium plus salmeterol–fluticasone group (P < 0.001) (25). Serious adverse events were similar across the 3 treatment groups.
Pulmonary rehabilitation but not disease management may improve health status and exercise capacity during the program in symptomatic adults with severe airflow obstruction. Conclusions based on published findings are problematic because exacerbations, hospitalizations, standardized health status measures, and exercise capacity were infrequently reported (Appendix Tables 4 and 5) (60–90). Most pulmonary rehabilitation programs contained 4 major components: endurance or exercise training, education, behavioral modification, and outcome assessment. Programs primarily emphasized endurance training and enrolled patients with severe to very severe COPD (mean FEV1, 31% to 54% predicted). Only 6 trials identified in the systematic review by Sin and colleagues (57) reported mean differences in SGRQ scores versus controls (pooled difference, 4.4 [CI, 0.3 to 8.4]), and 3 studies observed the average improvement between control and intervention greater than the 4-point minimally important difference (62, 67, 72). The average effect for the CRDQ dyspnea subscale was clinically significant (mean difference [vs. control] ranged from 0.2 to 14), but the increase in exercise tolerance measured by distance walked in 6 minutes was less than the 53-meter threshold that was determined to be clinically significant. Pulmonary rehabilitation did not reduce deaths, although sample size and study duration were insufficient to adequately evaluate this end point (5). A review of 6 small RCTs (n = 230) found that respiratory rehabilitation after acute COPD exacerbations in patients with severe airflow obstruction (baseline FEV1 <40% predicted) reduced hospitalizations (relative risk, 0.26 [CI, 0.12 to 0.54]; 3 trials reporting) and produced a clinically significant improvement in exercise capacity, as measured by the increased distance walked during the 6-minute walk test (64 to 215 meters; 4 trials reporting) and the SGRQ and CRDQ dyspnea subscales compared with usual care (3 trials reporting) (61).
Appendix Table 4.
Appendix Table 5.
Studies evaluating disease management used patient education, self-management with development of a treatment action plan, or enhanced follow-up with a respiratory health worker or pharmaceutical care coordinator (91–106). Appendix Tables 4 and 5 shows details of these studies. A total of 2911 patients with COPD were enrolled in 15 studies that lasted from 3 months to 1 year (5, 91, 105, 106). Average baseline FEV1 was less than 50% predicted, and all patients were taking inhaled bronchodilators. The only trial reporting exacerbations noted fewer episodes in the self-management plus telephone follow-up group (92). Pooled mortality rates from trials lasting at least 9 months and providing results did not differ between intervention and control (relative risk, 0.88 [CI, 0.66 to 1.18]) (Table 4). The RCTs of brief interventions found no evidence for a reduction in all-cause readmissions, and data from long-term or more intensive intervention RCTs were equivocal about health care utilization outcomes (91). The pooled difference in SGRQ health status scores versus usual care was less than clinically noticeable (weighted mean difference, −2.5 [CI, −4.8 to −0.1]). The relative risk and number of hospital readmissions did not differ (relative risk, 0.86 [CI, 0.68 to 1.08]).
Supplemental oxygen used during most of the daytime each day reduced deaths in patients with very severe airflow obstruction and daytime hypoxemia (107–114). Four trials had follow-up of 2 to 5 years (107–110). Baseline Pao2 ranged from 51 to 75 mm Hg. Interventions included using fixed doses of supplemental nocturnal oxygen for resting hypoxemia, titrating supplemental oxygen to maintain daytime arterial Pao2 between 60 and 80 mm Hg, using as-needed ambulatory oxygen in addition to home oxygen, and using short-burst oxygen therapy for activity-limiting dyspnea among patients with COPD who were not hypoxemic at rest.
Exacerbations or hospitalizations were rarely reported. Supplemental oxygen used for 15 or more hours daily to maintain a Pao2 greater than 60 mm Hg reduced deaths in 2 studies (n = 290) that enrolled persons with mean baseline FEV1 less than 30% and mean resting Pao2 of 55 mm Hg or less (relative risk, 0.61 [CI, 0.46 to 0.82]) (108, 109). In 2 additional trials (n = 211), supplemental oxygen (mean use, 9 to 13 hours per day) did not reduce deaths among individuals with similar spirometric values but daytime Pao2 greater than 60 mm Hg (relative risk, 1.16 [CI, 0.85 to 1.58]) (109, 110).
Three small short-term studies assessed the effect of ambulatory oxygen on respiratory health status (111–113). Mean changes in CRDQ scores and exercise tolerance did not achieve clinically detectable improvement. The number of hospitalizations over 6 to 12 months and urgent care visits did not differ among cylinder oxygen (mean, 2.2 hospitalizations [SD, 2.4]), cylinder air (mean, 1.8 hospitalizations [SD, 1.5]), and usual care (mean, 1.4 hospitalizations [SD, 1.0]) (112).
Evidence of intervention effectiveness was limited to individuals with both bothersome respiratory symptoms (especially dyspnea and frequent exacerbations) and an FEV1 less than 60% predicted. Almost all treatment trials enrolled participants with symptomatic COPD who were prone to exacerbations and had a mean FEV1 less than 50% predicted. No data were available to determine whether long-acting β2-agonists were effective in symptomatic individuals with FEV1 greater than 60% or prevented symptoms among asymptomatic individuals.
No treatment trial evaluated modifying therapy, instituting combination inhaled therapy, or monitoring disease status according to spirometric results. However, these are unlikely to be beneficial because earlier findings (http://www.ahrq.gov/clinic/tp/spirotp.htm) demonstrated that 1) clinical improvement is not closely associated with an individual's spirometric response to therapy; 2) treatments other than smoking cessation provide only a small change in long-term decline in lung function; 3) wide intraindividual variation exists in spirometric decline; 4) higher doses of inhaled therapies have not been shown to provide clinically significant improvement compared with lower doses; 5) combination therapy provided little to no benefit compared with monotherapy; and 6) interventions were not effective in asymptomatic persons.
Current evidence suggests that COPD treatment benefits are primarily related to reduced exacerbations among exacerbation-prone adults with activity-limiting dyspnea and FEV1 less than 60% predicted. Inhaled corticosteroids and long-acting bronchodilators seem to be of similar effectiveness in reducing exacerbations compared with short-acting bronchodilators, but they differ in their adverse effects. Evidence indicates that average improvement in respiratory health status is clinically insignificant, but some individuals achieve a noticeable improvement. Mortality reduction occurs with long-term supplemental oxygen in symptomatic patients with severe airflow obstruction and resting hypoxemia. Studies of oxygen inconsistently reported other outcomes. When reported, treatment-related improvements were typically small. Studies of pulmonary rehabilitation showed improvements in health status and dyspnea but not in walking distance during the program. Neither disease management nor ambulatory oxygen seem to have benefits.
Combination therapy with inhaled corticosteroids and long-acting β2-agonists was of borderline statistical significance in reducing exacerbations and improving health status compared with monotherapy. Compared with long-acting β2-agonists alone, combination therapy did not reduce mortality. Compared with corticosteroids alone, combination therapy produced a 1% to 2% absolute mortality benefit that was of borderline statistical significance. Reductions in hospitalizations versus long-acting monotherapies were generally small and were not consistently observed. Health status improvements were generally not clinically significant. Tiotropium, added to a long-acting β2-agonist or corticosteroid plus long-acting β2-agonist, did not reduce exacerbations or improve dyspnea versus tiotropium monotherapy (25).
Adverse effects of long-acting inhaled therapies were usually mild, although pneumonia may be more common with inhaled corticosteroids. There was no association with fractures, but trials were short in duration. Most trials used a treatment run-in period and enrolled exacerbation-prone persons who were previously receiving and tolerating long-acting inhaled therapy. Consequently, adverse effects, treatment adherence, and effectiveness may be different in clinical practice than in published trials. All-cause withdrawals and withdrawals due to adverse effects were fewer with long-acting inhaled therapies and combination therapies than with placebo and monotherapies, respectively, suggesting that the perceived benefits of long-acting inhalers outweigh harms.
In adults with mild to moderate airflow obstruction who did not report respiratory symptoms, treatment with ipratropium did not prevent symptom development. No studies evaluated treatment of asymptomatic individuals with severe airflow obstruction. Among symptomatic participants with FEV1 greater than 50% but less than 80% or those with normal airflow but having chronic sputum production, 7 large studies of inhaled corticosteroids or anticholinergics that lasted at least 1 year found little to no improvement in exacerbations, health status, hospitalizations, or deaths (12, 29, 40, 43, 45, 47; http://www.ahrq.gov/clinic/tp/spirotp.htm).
Respiratory symptoms are common, clinical examination has poor accuracy for determining airflow obstruction severity (http://www.ahrq.gov/clinic/tp/spirotp.htm), and few adults have airflow obstruction severe enough that treatments have demonstrated effectiveness. Therefore, adopting a strategy that targets use of long-acting inhaled corticosteroids or bronchodilators as monotherapy to individuals reporting activity-limiting respiratory symptoms (especially dyspnea) and having an FEV1 less than 60% would maintain benefits and minimize unnecessary testing or ineffective treatment. Pulmonary rehabilitation in these individuals may be beneficial, and long-term nocturnal supplemental oxygen in the presence of resting hypoxemia can reduce mortality. Spirometry to monitor disease status or modify therapy has not been evaluated in randomized trials. Studies are required to determine whether the relative effectiveness among therapies varies according to an individual's baseline or follow-up spirometry findings.
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Christian Medical College and Hospital Ludhiana,India
November 6, 2007
Compassionate care for COPD patients
Two major problems facing the clinician treating the stable COPD patient are diagnosis and attitude. First, COPD is underdiagnosed.1,2 Even when diagnosed, the clinical importance of the disease is often underestimated. 3 This underestimation might reflect, in part, an inappropriate inclination of many clinicians toward therapeutic nihilism for COPD patients. This attitude might be based on the historical approach toward such patients as stated by Williams in Middle and Old Age (Oxford Medical Publications), quoted by Fletcher and colleagues4: "Chronic bronchitis with it accompanying emphysema is a disease on which a good deal of wholly unmerited sympathy is frequently wasted. It is a disease of the gluttonous, bibulous, otiose, and obese and represents a well-deserved nemesis for these unlovely indulgences . . . the majority of cases are undoubtedly due to surfeit and self-indulgence." This attitude toward COPD patients is inappropriate not only for its lack of compassion, but, at the present time, because therapeutic interventions for stable patients can result in substantial clinical benefit.
1 Mannino DM, Gagnon RC, Petty TL, Lydick E. Obstructive lung disease and low lung function in adults in the United States: data from the National Health and Nutrition Examination Survey, 1988"“1994. Arch Intern Med 2000; 160: 1683"“89.
2 Mannino DM, Homa DM, Akinbami LJ, Ford ES, Redd SC. Chronic obstructive pulmonary disease surveillance"”United States, 1971- 2000. MMWR Surveill Summ 2002; 51: 1"“16.
3 Jones PW. Issues concerning health-related quality of life in COPD. Chest 1995; 107 (suppl): 187"“193.
4 Fletcher C, Peto R, Tinker C, Speizer FE. The natural history of chronic bronchitis and emphysema. New York: Oxford University Press, 1976.
Christian Medical College and Hospital, Ldh, Pb, In
November 9, 2007
Give Benefit of Doubt to Patients with COPD
COPD is a leading cause of morbidity and mortality in the adult population world-wide and affects 6% and 3% of the male and female population in the United States respectively 
Patients with COPD have frequent exacerbations that may require hospitalization. There are various reasons for this. Failure to comply with treatment plan, in the form of not taking the medications on time or not using the prescribed oxygen therapy for adequate no of hours at home, or not using the non invasive ventilation as prescribed to them at home. Domiciliary oxygen therapy improves survival, exercise performance, and daily activities,
Another reason is because of frequent lower respiratory tract infection, pneumonias and spontaneous pneumothorax, which is common in patients with advanced bullous disease. Timely intervention and diagnosis of treatable causes of COPD can help reduce morbidity and mortality. More over these patients may have co morbid conditions like diabetes mellitus, renal failure, hypertension, obesity and cardiac arrhythmias , cor pulmonale, septicemia.[4,5,6].
Patients with these above conditions can be easily mistaken for end stage respiratory failure, and the physician may not be aggressive in admitting the patient to intensive care unit (ICU) and resuscitating them. Poor financial condition of the patient may be an additional factor for their no getting admitted to ICU. While the fact is that they may respond and recover if vigorous ICU care is instituted, including elective intubation, ventilation and adequate coverage with broad spectrum antibiotics. Wise use of corticosteroids, bronchodilators and anticolinergics, physiotherapy, lung volume reduction surgery and bullectomy might help them recover fast. Infection, hypoxia, hypercarbia and co morbid conditions should be treated aggressively.
It would be wise to admit all COPD patients to ICU and investigate and treat. Guarded but not negative prognosis should be maintained. A poor outcome should not deter the physician from admitting and treating patients with COPD. Patients should be immediately hospitalised if there is an exacerbation complicated by severe dyspnoea or respiratory failure 
1 Celli B, Snider GL, Heffner J, et al. 1995. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995;152:S77- S120.
2 Petty TL, Finigan MM. Clinical evaluation of prolonged ambulatory oxygen therapy in chronic airway obstruction. Am J Med 1968: 45:242-252.
3 FusoL, Incalzi RA, Pistclli R, et al. Predicting mortality of patients hospitalised for acutely exacerbated chronic obstructive pulmonary disease. Am J Med 1995;98:272-277.
4 Niederman MS, Bass JB Jr, Campbell GD, et al. Guidelines for the i n i t i a l management of adults with community acquired pneumonia. Am Rev Respir Dis 1993:148:1418-1426.
5 Tsang KWT, Lam WK. The management of community acquired pneumonia. HK Pract 1997:19:80-88.
6 B r i t i s h Thoracic Society. Public Health Laboratory Service. Community acquired pneumonia in adults in British hospitals in 1982-3: a survey of aetiology, mortality, prognostic factors and outcome. QJ Med 1987; 62:195-220.
7 Martin J Wildman et al. Implications of prognostic pessimism in patients with chronic obstructive pulmonary disease (COPD) or asthma admitted to intensive care in the UK within the COPD and asthma outcome study (CAOS): multicentre observational cohort study. BMJ, doi:10.1136/bmj.39371.524271.55 (published 1 November 2007)
University of Missouri-Columbia
November 11, 2007
A missing piece of the puzzle
Since no studies have shown a clear-cut survival benefit with any inhaled therapies in COPD, the next most important hard outcome would be hospitalization rates. Wilt et al concluded that the reductions in hospitalizations with inhaled therapies were inconsistent and evidence did not permit definitive conclusions about relative effectiveness. I agree that that is true with long-acting beta-agonists (LABA) and inhaled corticosteroids (ICS). However, recent meta-analyses have shown that tiotropium consistently reduced hospitalization rates in moderate-to-severe COPD. (1,2) Pooled analyses including recent studies such as TORCH (3) were conducted to update previous studies and tiotropium is still the only inhaled therapy that consistently and significantly reduced hospitalizations. (Figures are available at http://pulmccm.blogspot.com) Although TORCH study showed a statistically significant reduction in hospitalizations with combined LABA and ICS, there aren't enough data to conduct a pooled analysis on COPD related hospitalizations. In a recent Canadian study, tiotropium also showed reduced need for hospitalization, when combined with an ICS and LABA, but not with a LABA alone. (4) In conclusion, currently available evidence suggests that tiotropium and/or combined ICA/LABA should be the drug of choice in stable moderate-to-severe COPD.
1. Barr RG, Bourbeau J, Camargo CA, Ram FS. Tiotropium for stable chronic obstructive pulmonary disease: A meta-analysis. Thorax. 2006;61:854-62.
2. Oba Y. Cost Effectiveness of Long-Acting Bronchodilators for Patients with Moderate to Severe Chronic Obstructive Pulmonary Disease. Mayo Clin Proc 2007:82(5);575-82.
3. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356:775-89.
4. Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2007;146:545-55.
Timothy J. Wilt
Minneapolis VA Center for Chronic Disease Outcomes Research
December 21, 2007
Re: A missing piece of the puzzle
We thank Dr Oba for his comments on our paper on COPD. Dr. Oba concludes that tiotropium is the preferred therapy for management of chronic stable COPD based on a meta-analysis of 4 tiotropium studies demonstrating a 6% risk difference (RD) (95%CI,-10,-2) in the annual rate of hospitalizations compared to placebo as well as the lack of a statistically significant reduction against placebo for studies of inhaled corticosteroids (ICS) or long-acting inhaled beta agonists (LABA) that reported this outcome (1). We described similar findings in our manuscript. "The proportion of participants requiring hospitalization for COPD was lower with tiotropium than with placebo (RD, -2% [CI,-4 to -1%]" (2).
We identified 42 eligible RCTs of inhaled therapies. However, few reported on hospitalizations. When reported, reductions were not consistently observed and very few studies assessed comparative effectiveness across categories of long-acting inhalers. Of the 10 eligible tiotropium studies just 5 reported hospitalizations and 4 used placebo controls. Only 1 of these studies demonstrated statistically significant benefit. The difference in effectiveness estimates for annual rates compared to proportion of participants hospitalized is likely due to some individuals requiring recurrent hospitalizations. The clinical significance of these pooled reductions in hospitalizations and preferred analytic method are not known. Furthermore, investigators have demonstrated that selective study or outcome reporting (publication bias) results in biased (and more positive) effectiveness estimates (3). Therefore, we do not agree that the above findings are sufficient to draw comparative effectiveness conclusions.
Data for other outcomes did not support the superiority of a particular class of long-acting inhaler. Many patients with symptomatic COPD place an equal or greater value on obtaining a noticeable improvement in respiratory health status or reduction in exacerbations rather than hospitalizations. No studies directly compared tiotropium versus ICS. Tiotropium did not provide a clinically noticeable improvement in the average respiratory health status scores versus placebo and there were no statistical or clinical differences versus LABA. Based on pooled results of the 2 comparative studies, tiotropium did not reduce exacerbations compared to LABA. None of the inhaled monotherapies reduced mortality versus placebo (relative risk [RR], tiotropium=0.94 (CI,0.60-1.47). Combined LABA and ICS reduced mortality in relative terms (RR 0.82 (0.69- 0.98). The absolute reduction was 1% and not statistically significant.
Based on the available evidence, we conclude that the current level of evidence does not allow a determination of whether one long-acting inhaled therapy (or combinations of these therapies) is superior to another for management of chronic stable COPD (4). Additional large, long- term randomized trials comparing relative effectiveness and harms are needed.
1) Oba Y. A Missing piece of the puzzle. Ann Intern Med XXX
2) Wilt TJ, Niewoehner, MacDonald D, Kane RL. Management of Stable Chronic Obstructive Pulmonary Disase: A Systematic Review for a Clinical Practice Guideline. Ann Intern Med. 2007;147:639-653.
3) Lau J, Ioannidis JPA, Terrin N, Schmid CH, and Olkin I. The case of the misleading funnel plot BMJ. 2006;333:597-600.
4) Qaseem A, Snow V, Shekelle P, Sherif K, Weinberger S, Wilt TJ and Owens DK. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2007;147:633-8.
Consultancies D. Niewoehner (Boehringer Ingelheim, AstraZeneca, GlaxoSmithKline, Sanofi Aventis, Schering-Plough, Adams Respiratory THerapeutics). Honoraria: D. Niewoehner (Pfizer Inc., Boehringer Ingelheim). Grants received: D. Niewoehner (Boehringer Ingelheim, GlaxoSmithKline).
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