Andrea Gershon, MD, MSc; Ruth Croxford, MSc, PStat; Teresa To, PhD; Matthew B. Stanbrook, MD, PhD; Ross Upshur, MD, MSc; Paula Sanchez-Romeu, BMath, MMath; Thérèse Stukel, PhD
Disclaimer: The opinions, results, and conclusions reported in this paper are those of the authors and are independent of the funding sources. No endorsement by the Institute for Clinical Evaluative Sciences or the Ontario Ministry of Health and Long-Term Care is intended or should be inferred.
Acknowledgment: The authors thank Brogan, Ottawa, Ontario, Canada, for the use of their Drug Product and Therapeutic Class Database.
Grant Support: By the Government of Ontario; a Career Scientist Award from the Ontario Ministry of Health and Long-Term Care and a Research Fellowship from the Canadian Institutes of Health Research, Institute of Population and Public Health, and The Public Health Agency of Canada (Dr. Gershon); and the Dales Award in Medical Research from the University of Toronto, (Dr. To). Support was also provide by the Institute for Clinical Evaluative Sciences, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care.
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-1643.
Reproducible Research Statement:Study protocol and statistical code: Available from Ms. Croxford (e-mail, email@example.com). Data set: Not available.
Requests for Single Reprints: Andrea Gershon, MD, MSc, Institute for Clinical Evaluative Sciences, G106, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Gershon and Stukel, Ms. Croxford, and Ms. Sanchez-Romeu: Institute for Clinical Evaluative Sciences, G106, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
Dr. To: Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
Dr. Stanbrook: Asthma & Airway Centre, Toronto Western Hospital, 7th Floor, East Wing, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada.
Dr. Upshur: Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Room A100, Toronto, Ontario M4N 3M5, Canada.
Author Contributions: Conception and design: A. Gershon, R. Croxford, M.B. Stanbrook, R. Upshur, T. Stukel.
Analysis and interpretation of the data: A. Gershon, R. Croxford, M.B. Stanbrook, R. Upshur, P. Sanchez-Romeu, T. Stukel.
Drafting of the article: A. Gershon, R. Croxford, R. Upshur, P. Sanchez-Romeu.
Critical revision of the article for important intellectual content: A. Gershon, R. Croxford, T. To, M.B. Stanbrook, R. Upshur, T. Stukel.
Final approval of the article: A. Gershon, R. Croxford, T. To, M.B. Stanbrook, R. Upshur, P. Sanchez-Romeu, T. Stukel.
Statistical expertise: R. Croxford, T. To, P. Sanchez-Romeu, T. Stukel.
Obtaining of funding: A. Gershon.
Administrative, technical, or logistic support: R. Croxford.
Collection and assembly of data: A. Gershon, R. Croxford, P. Sanchez-Romeu.
Gershon A, Croxford R, To T, Stanbrook MB, Upshur R, Sanchez-Romeu P, et al. Comparison of Inhaled Long-Acting β-Agonist and Anticholinergic Effectiveness in Older Patients With Chronic Obstructive Pulmonary Disease: A Cohort Study. Ann Intern Med. 2011;154:583-592. doi: 10.7326/0003-4819-154-9-201105030-00003
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Published: Ann Intern Med. 2011;154(9):583-592.
Appendix: Effectiveness of Long-Acting Inhaled β-Agonists and Anticholinergics in Older Patients With COPD
Chronic obstructive pulmonary disease (COPD), a largely preventable and manageable respiratory condition, affects an estimated 12% to 20% of adults. Long-acting inhaled β-agonists and anticholinergics have both been shown to improve COPD outcomes and are recommended for moderate to severe disease; however, little is known about their comparative effectiveness.
To compare survival in older patients with COPD who initially receive inhaled long-acting β-agonists with that of patients who receive anticholinergics.
Population-based, retrospective cohort study.
Patients aged 66 years or older (who carry the largest burden of COPD and for whom data were available) who met a validated case definition of COPD on the basis of health administrative data and were newly prescribed an inhaled long-acting β-agonist or a long-acting anticholinergic (but not both) between 2003 and 2007. Patients were followed for up to 5.5 years.
The primary outcome was all-cause mortality.
A total of 46 403 patients with COPD (mean age, 77 years; 49% women) were included. Overall mortality was 38.2%. Mortality was higher in patients initially prescribed a long-acting anticholinergic than in those initially prescribed a long-acting inhaled β-agonist (adjusted hazard ratio, 1.14 [95% CI, 1.09 to 1.19]). Rates of hospitalizations and emergency department visits were also higher in those initially prescribed a long-acting anticholinergic.
Patients were classified as having COPD on the basis of health administrative records, which did not contain information about lung function.
Older adults initially prescribed long-acting inhaled β-agonists for the management of moderate COPD seem to have lower mortality than those initially prescribed long-acting anticholinergics. Further research is needed to confirm these findings in younger patients and in a randomized, controlled trial.
Government of Ontario, Canada.
Long-acting inhaled β-agonists and anticholinergic agents are both used to treat chronic obstructive pulmonary disease (COPD). Whether one or the other is better for initial therapy is not known.
Patients with physician-diagnosed COPD were identified in a public health administrative database by using a computer algorithm. Patients initially prescribed a long-acting anticholinergic agent had more hospital visits and higher mortality rates than those initially prescribed a long-acting β-agonist.
Patients were identified as having COPD according to administrative data, not clinical guidelines. Lung function testing was not available.
Further study regarding the relative benefits of long-acting anticholinergics and β-agonists for treatment of COPD is warranted.
Chronic obstructive pulmonary disease (COPD) is a largely preventable and manageable respiratory condition that affects an estimated 12% to 20% of adults older than 40 years (1, 2). It is also the fifth leading cause of death in the world and is projected to be the fourth by 2030 (3, 4). Thus, effective, evidence-based strategies to improve COPD outcomes are crucial.
Medications are a mainstay of COPD management. Long-acting β-agonists, such as salmeterol and formoterol, and long-acting anticholinergics, also referred to as “muscarinic antagonists” (of which only tiotropium bromide is currently available for public use), are recommended for the management of moderate to severe COPD (5). Randomized, controlled trials (RCTs) (6, 7) have shown that both types of drug can decrease exacerbations and hospitalizations and improve symptoms, lung function, quality of life, and possibly mortality compared with placebo. However, little is known about their comparative effectiveness in actual practice. This information would allow patients to initiate therapy with the long-acting medication most likely to provide the greatest benefit, and possibly avoid use of additional medications that would increase risk, inconvenience, and cost (5).
The purpose of our population-based, retrospective, observational cohort study of older patients with COPD was to compare the effectiveness of long-acting anticholinergics and long-acting β-agonists in terms of survival. Older patients were studied because they carry the highest burden of COPD and because population-wide medication records were available for patients aged 65 years or older.
We conducted our study by using health administrative data from Ontario, a province of Canada with a diverse, multicultural population of approximately 12 million, including about 1.8 million persons aged 65 years or older. The ethics committee of Sunnybrook Health Sciences Centre, Toronto, Ontario, approved our study.
Residents of Ontario have universal public health insurance under the Ontario Health Insurance Plan, the single payer for all medically necessary services across virtually all residents, providers, and hospitals. Service details are captured in health administrative databases, which can be linked on an individual level to provide a complete health services profile for each resident. The Registered Persons Database contains basic demographic information and dates of death. The Ontario Drug Benefit Program database contains prescription claim records for all residents aged 65 years or older. Publicly funded prescriptions are subject to a small, means-tested copayment, which does not affect the rate at which they are obtained (8). The Discharge Abstract Database and National Ambulatory Care Reporting System Database of the Canadian Institute of Health Information contain information on all discharges from acute care hospitals, same-day surgical procedures, and emergency department visits. The Ontario Health Insurance Plan Physician Claims database contains information about all services provided by fee-for-service physicians and “shadow billings” for physicians paid under alternate payment plans.
We also used the Canadian Community Health Survey, a national, cross-sectional, population-based survey conducted by Statistics Canada every 2 years. Responses to the 2001, 2003, and 2005 surveys were linked to the health administrative databases on an individual level to obtain additional patient information, including smoking history.
We included patients who met a previously validated case definition of physician-diagnosed COPD on the basis of health administrative data (9), were aged 66 years or older, and filled a first prescription for either a long-acting anticholinergic or long-acting β-agonist between 1 July 2003 (when long-acting anticholinergics were first commonly used in the community) and 31 March 2007. Compared with real-world clinical evaluation by a physician (which may or may not have included spirometry ), the case definition of 1 hospitalization or 3 ambulatory care claims for COPD had a positive predictive value of 81.3% in adults aged 35 years or older (9) and 86.3% in adults aged 65 years or older (unpublished data). This value was probably even higher in patients who met the case definition and were prescribed a long-acting anticholinergic or long-acting β-agonist, such as those studied here. The date of filling a first prescription was used as the study index date. Only new users, defined as those who had not filled a prescription for a long-acting anticholinergic or long-acting β-agonist in the previous 12 months (including a combination medication that contained a long-acting β-agonist), were included to avoid bias due to either better outcomes among patients who had been receiving their index medication for a longer time or worse outcomes among patients who had been receiving therapy with other long-acting medications that had failed. The study was restricted to patients aged 66 years or older to allow us to look at medication use in the past year.
We obtained demographic, COPD-related, and general care–related characteristics from the health administrative databases (Table 1 and Appendix Table 1). Severity of COPD was captured by using information from hospitalizations, emergency department visits, ambulatory care visits, prescription drug use, and interventions before the index date. Socioeconomic status was inferred from neighborhood income, which was derived from postal code and census data (11). Comorbidity was based on diagnostic information in health services records from the 2 years before the index date and was characterized by using the Johns Hopkins Adjusted Clinical Group Case-Mix System (12, 13).
Appendix Table 1.
The primary outcome was all-cause mortality. Secondary outcomes were hospitalizations and emergency department visits for COPD, related respiratory diseases (influenza, acute bronchitis, or pneumonia), and cardiovascular disease (acute myocardial infarction, congestive heart failure, ischemic heart disease, cardiac arrhythmias, or cerebrovascular disease). Hospitalizations and emergency department visits were analyzed as a combined end point with mortality because mortality was common and the factors that caused it were probably exacerbations of those that caused a hospitalization or emergency department visit (making censoring for mortality inappropriate). Patients were followed beginning 7 days after their index prescription, to allow time for patients to start taking their medication and for it to start taking effect (14). Patients who did not die were censored on 15 March 2009. All-cause mortality was used because cause of death was not available in the health administrative data.
We used propensity score matching to compare patients with similar observed characteristics, all of whom were potential candidates for both treatments (15). Patients initially prescribed a long-acting anticholinergic were matched 1:1 with those initially prescribed a long-acting β-agonist on the basis of age (±1 year), sex, asthma status, number of COPD medication prescriptions filled in the previous year, and propensity score. An absolute standardized difference between variables of less than 10% was accepted as adequate balance (16).
Outcomes were compared by using Cox proportional hazards regression analysis, adjusted for matched pairs. All statistical tests were 2-sided, with statistical significance defined as a P value less than 0.05. Analyses were performed by using SAS, version 9.1 (SAS Institute, Cary, North Carolina). The Appendix contains additional information on propensity score methodology.
To further ensure that variables not available in the health administrative data, including smoking status, were balanced between treatment groups, we performed a sensitivity analysis by using propensity score calibration and additional information from the Canadian Community Health Survey (17) (Appendix).
We conducted several sensitivity analyses to evaluate the robustness of our results. The main analyses were repeated by using a standard proportional hazards regression that adjusted for all covariates, rather than matching on the propensity score. A complementary analysis, which compared the on-treatment effects of long-acting β-agonists and long-acting anticholinergics, was also conducted on the basis of current patient use of these medications rather than initial choice of treatment. This was done with a time-on-treatment analysis of the effect of medication exposure by using a standard time-varying proportional hazards analysis with adjustments for all of the variables used to calculate the propensity score.
The propensity score–matched analyses were also repeated on subsets of the cohort to look for consistency in the results. First, we examined the subsets of the cohort who had or had not previously received spirometry, to determine whether more or less certainty about the COPD diagnosis influenced the results. The original analysis was also stratified by factors of a priori interest, including sex, asthma status, number of prescriptions for COPD medication filled in the previous year, inhaled corticosteroid use, and diagnosis of congestive heart failure.
We conducted 2 sensitivity analyses to check assumptions made in the main analyses. One was that follow-up should not begin until 7 days after filling the index prescription, to allow time for patients to start taking their medication and for the medication to start taking effect. To check this, we repeated the analysis, including outcomes that occurred within this period. Another assumption was that hospitalizations and emergency department visits were along the causal pathway to the primary outcome of death and therefore should be combined with it as a composite outcome. To check this, we examined time to first COPD hospitalization and time to first COPD emergency department visit as separate outcomes.
Finally, we determined whether it was plausible that an unmeasured confounder or the inclusion of persons without COPD, due to misclassification error, was responsible for the observed results by using an array approach. The rate ratio of a theoretical, unmeasured confounder and the imbalance of this confounder between the study cohorts were both varied to see at what point the observed hazard ratio was reduced to 1.0 (18). The same approach was used to estimate the effects of misclassification due to the case definition (Appendix).
Our study was funded by the Government of Ontario and the Institute for Clinical Evaluative Sciences, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. The funding sources had no role in study design, collection, analysis, interpretation of data, writing of the report, or the decision to submit the report for publication.
We found 28 563 new users who were initially prescribed a long-acting anticholinergic and 17 840 who were initially prescribed a long-acting β-agonist and met the validated case definition of COPD, on the basis of the health administrative data (Appendix Figure). Compared with users of long-acting β-agonists, users of long-acting anticholinergics were less likely to be female or have asthma and less likely to have filled a prescription for a respiratory antibiotic or oral corticosteroid in the previous year, seen a specialist, or received spirometry (Table 1).
COPD = chronic obstructive pulmonary disease.
The propensity score provided fair discrimination between treatment groups (c statistic = 0.66). Matching produced 15 532 pairs. After matching, the long-acting anticholinergic and long-acting β-agonist groups did not significantly differ (Table 1 and Appendix Table 2). Within the matched cohorts, median follow-up times for patients initially prescribed long-acting anticholinergics or long-acting β-agonists were 3.2 and 3.3 years, respectively (maximum, 5.5 years). Overall, 39.9% of patients initially prescribed a long-acting anticholinergic and 36.5% of patients initially prescribed a long-acting β-agonist died during the follow-up period (Table 2). Appendix Table 3 shows absolute survival by year. The Figure shows survival, by initially prescribed medication.
Appendix Table 2.
Appendix Table 3.
Overall, patients who were initially prescribed a long-acting anticholinergic had a modest but significantly higher adjusted rate of death (adjusted hazard ratio, 1.14 [95% CI, 1.09 to 1.19]) and all other outcomes than those prescribed a long-acting β-agonist (Table 2). No evidence indicated that the hazard ratios changed over time. The results of the calibrated propensity score analysis were consistent with those of the main analysis (Appendix).
The results from the standard proportional hazards regression models that included all of the covariates were similar to the results from the propensity score models (Table 2). The time-on-treatment analysis similarly found that patients currently receiving a long-acting anticholinergic were significantly more likely to die than those currently receiving a long-acting β-agonist, which confirms our main results (Table 3).
Separate analyses of patients who had or had not received previous spirometry found no significant difference in results between these subsets (Table 4). An initial prescription for long-acting β-agonists was also consistently associated with improved survival when results were stratified by sex, asthma status, inhaled corticosteroid use, congestive heart failure, and number of prescriptions for COPD medication filled in the previous year (Appendix Table 4). Of interest, stratification by number of prescriptions for COPD medication suggested that the relative survival of those initially treated with a long-acting β-agonist, compared with a long-acting anticholinergic, may have been higher in patients with fewer prescriptions (hazard ratio for those with 0 to 2 prescriptions, 1.23 [CI, 1.13 to 1.33]; 3 to 10 prescriptions, 1.14 [CI, 1.06 to 1.23]; >10 prescriptions, 1.07 [CI, 1.00 to 1.15]).
Appendix Table 4.
An initial prescription for a long-acting β-agonist continued to be associated with better outcomes than one for a long-acting anticholinergic when the analysis was repeated, first with the inclusion of outcomes that occurred within 7 days of the index prescription being filled and then with COPD hospitalizations and emergency department visits for COPD analyzed as separate outcomes (Table 2 and Appendix Table 5).
Appendix Table 5.
The rate ratio of a theoretical, unmeasured potential confounder would have to be at least 2.0, or the imbalance due to this confounder more than 15%, to reduce the observed hazard ratio to 1.0. Likewise, if all patients who were misclassified as having COPD were in the long-acting β-agonist group and were 30% less likely to die than those with true COPD, or if they were all in the long-acting anticholinergic group and were at least 30% more likely to die than those with true COPD, the observed hazard ratio would be reduced to 1.0 (Appendix).
We conducted an observational, longitudinal, population-based study of new use of long-acting anticholinergics and long-acting β-agonists by older patients who met a validated case definition of COPD on the basis of health administrative data. Patients who were initially prescribed a long-acting anticholinergic seemed to have a 14% higher adjusted mortality rate than those initially prescribed a long-acting β-agonist and were also more likely to be hospitalized or to visit an emergency department for COPD or a related condition. The incremental risk associated with long-acting anticholinergics seemed to be independent of patient sex or coexisting medical conditions or whether the diagnosis of COPD was confirmed with spirometry. Thus, our findings suggest that long-acting β-agonists may be more effective than long-acting anticholinergics at improving survival in older patients with COPD. To our knowledge, our observational study is the first to directly compare mortality with long-acting β-agonists and mortality with long-acting anticholinergics in a large population of older patients with COPD.
A few small RCTs and meta-analyses that compared such outcomes as lung function or health status between patients receiving long-acting β-agonists and those receiving long-acting anticholinergics have yielded conflicting results. However, most found that both drug classes were equally effective in preventing exacerbations and hospitalizations (19–22). A larger RCT designed to examine the relative efficacy of long-acting β-agonists versus long-acting anticholinergics on exacerbations (but not mortality, as in our study) has been completed (23), but the results have not yet been released.
Although RCTs remain the gold standard for the study of the efficacy of COPD medication, observational studies, such as ours, provide complementary information on medication effectiveness (which might differ from RCT results) for several reasons. First, RCTs often have limited generalizability because they exclude patients who are part of the population to which the therapy will be applied, such as those with severe disease or comorbidity (24). For example, our study examined a large, older, frailer population—many of whom would have been excluded from previous RCTs. Second, RCTs may recruit patients who are not new users of medications (more than one half of the patients enrolled in the TORCH [TOwards a Revolution in COPD Health] trial , which studied the effectiveness of inhaled corticosteroids and long-acting β-agonists, had used at least 1 of these medications in the year before study entry) and who, because they tolerated the regimen and volunteered to receive it in a study, may be more likely to have favorable outcomes. To avoid this, we examined only new users of medication. Finally, RCTs are often not large enough or long enough to look at relatively rare events, such as mortality. Our study followed tens of thousands of patients for up to 5.5 years.
Our study suggests a relative difference in mortality between patients initially prescribed long-acting anticholinergics and those prescribed long-acting β-agonists, but it was not designed to determine the reasons why. One possibility is that both types of drug effectively reduce mortality, but long-acting β-agonists do so more than long-acting anticholinergics. A second possibility is that long-acting β-agonists do not or only marginally reduce mortality, whereas long-acting anticholinergics increase mortality. The latter hypothesis is supported by several studies and meta-analyses (25–30), which found an increase in all-cause and cardiovascular mortality associated with inhaled anticholinergics but not with inhaled β-agonists. However, few of these studies focused specifically on long-acting (as opposed to short-acting) medications. In contrast, a recent meta-analysis (6, 31), which included the large UPLIFT (Understanding Potential Long-term Impacts on Function with Tiotropium) study, found no evidence of increased mortality associated with long-acting anticholinergics; however, this work has the same limitations as the RCTs it was based on, most notably limited generalizability and the inclusion of patients who had previously received the study medications.
Our study has limitations. First, a drawback of all observational studies is potential confounding by indication or by disease severity. Because our data did not contain a precise measure of disease severity (such as lung function), we cannot be sure that such confounding did not occur. However, we consider confounding unlikely because we controlled for many prognostically important variables. As further assurance that an unmeasured confounder, such as smoking, was accounted for, a propensity score calibration analysis was used to confirm the results. In addition, a potential unmeasured confounder would have to have either a much greater association with death than that of smoking or a greater imbalance between the cohorts than that seen for any of the variables except asthma to negate our results (32). Such a confounder also could not be strongly correlated with any of the other variables (such as asthma) already adjusted for in the analysis.
Second, cases of other respiratory diseases, most likely asthma, could have been misclassified as COPD. In an extreme scenario in which all such misclassification occurred in the long-acting β-agonist group, patients incorrectly classified as having COPD would have had to be about 30% less likely to die than those with true COPD to explain our results. Because all-cause mortality has been estimated to be 27% lower in patients aged 65 years or older with asthma than in patients of the same age with COPD (2, 33), misclassification could explain our observed results. In a second extreme scenario, in which misclassification only occurred in the long-acting anticholinergic group, patients misclassified as having COPD would have had to be about 30% more likely to die than those with true COPD to explain our results. If the misclassified patients had asthma, mismanagement of their disease could have increased their risk for death. However, this is unlikely to have caused a 30% increase in mortality in practice, especially because a large proportion of patients receiving a long-acting anticholinergic were also receiving asthma medications, and long-acting anticholinergics seem to benefit patients with asthma (34). Because the medication groups were matched on a codiagnosis of asthma, neither extreme scenario is likely.
Finally, patients were not completely adherent to their index medication regimen and often received the other study medication, a situation that is common in the real world. However, the results of a time-varying analysis, which looked only at current use of medication, were consistent with our main results and, on average, patients spent more time taking the initially prescribed drug than taking the alternative (Appendix).
In summary, we conducted a population-based, retrospective, observational study of new use of long-acting anticholinergics and long-acting β-agonists in older patients who met a validated case definition of COPD on the basis of health administrative data. We found that patients initially prescribed a long-acting anticholinergic seemed to have a 14% higher adjusted mortality rate than those initially prescribed a long-acting β-agonist. This suggests that long-acting β-agonists might be a better initial therapy for patients with moderate to severe COPD. Future research is needed to confirm these findings in RCTs and in younger patients. Research is also needed to examine the relative safety profiles of these medications so that their risk–benefit ratios can be compared.
The Appendix Figure shows how patients in the administrative health databases were selected for inclusion in our study.
We used propensity score methodology to control for confounding by baseline cohort characteristics. The propensity score reflects the probability that a given patient was initially prescribed a long-acting anticholinergic, given that patient's particular pattern of baseline covariates, and was calculated by using logistic regression. A set of 57 covariates, which covered patient demographic characteristics, COPD severity, and overall health, were used to calculate the propensity score. Appendix Table 1 shows the variables used and the associated odds ratios.
One-to-one matching between patients in the long-acting anticholinergic and long-acting β-agonist cohorts was based on the propensity score and was made only if both scores agreed to within a “caliper” of 0.2 times the SD of the scores. Matching on the propensity score allows unbiased estimation of the treatment effect, to the extent that unmeasured confounders are correlated with the measured covariates. Matching also restricts the analysis to those who are eligible to receive either treatment. Patients were also matched on the basis of age (±1 year), sex, asthma status, and number of COPD medication prescriptions filled in the previous year. Each matched pair was unique; data from unmatched patients were excluded.
After matching, the 2 treatment groups were compared with respect to each of the measured covariates to determine the adequacy of the model used to estimate the propensity score. A properly constructed propensity score ensures that the 2 matched treatment groups are comparable with respect to all of the measured covariates. Appendix Table 2 shows the standardized between-group differences and P values before and after matching. After matching, all standardized differences were less than 10%, and all P values were far removed from statistical significance, which indicates good balance.
Cox proportional hazards survival analysis was used to compare outcomes for patients in the long-acting anticholinergic treatment cohort with those in the long-acting β-agonist cohort, taking membership in a matched pair into account.
Our primary analysis found improved outcomes among patients initially treated with a long-acting β-agonist compared with those initially treated with a long-acting anticholinergic (Table 2). To supply context for the reported hazard ratios, Table 2 also presents the absolute difference in survival at 3 years. Appendix Table 3 contains more complete information, showing the percentage of patients in the group initially treated with long-acting β-agonists who survived to the end of each of the 5 years, and the survival difference between the treatment groups. The percentage of patients who survived in the long-acting anticholinergic cohort can be calculated as the percentage who survived in the long-acting β-agonist cohort minus the difference in survival.
As a check that variables not available in the health administrative data were balanced between the treatment groups, we performed a sensitivity analysis by using propensity score calibration (17). A representative subcohort of 694 patients (250 from the long-acting β-agonist cohort and 444 from the long-acting anticholinergic cohort) participated in the Canadian Community Health Survey and had data on smoking status, including exposure to secondhand smoke, body mass index, immigration status, and self-reported health, to augment the data from their original health administrative variables. A gold standard propensity score was calculated for these patients, on the basis of their original data plus the additional data. This gold standard score was compared with their previous propensity score, using ordinary least-squares regression, to obtain the relationship between the 2 scores. The resulting equation was then used to transform the propensity scores of all study patients (not just those with additional data) into gold standard scores. Finally, the matching and outcome analyses were repeated, as with the primary analysis. Results of the calibrated propensity score analysis were consistent with the main analysis (Appendix Table 6).
Appendix Table 6.
We performed several additional analyses to check the robustness of the results. Appendix Tables 4, 5, 6, 7, and 8 provide supporting information and results from these analyses.
Appendix Table 7.
Appendix Table 8.
The analyses were repeated by using a standard proportional hazards regression that adjusted for all covariates rather than the matched propensity score analysis (Table 2). Appendix Table 5 presents the hazard ratios for each covariate in this analysis.
Appendix Table 6 presents the results of the propensity score–matched analysis, stratified by sex, asthma status, number of COPD prescriptions filled in the previous year, inhaled corticosteroid use, and a diagnosis of congestive heart failure. In each stratified analysis, long-acting β-agonists continued to be associated with improved survival.
Appendix Table 7 provides the results obtained when all analyses (calculation of the propensity score, matching, and the matched proportional hazards regression) were repeated with the inclusion of outcomes that occurred within 7 days of the index prescription being filled. Including these outcomes did not significantly change the study results.
A time-on-treatment analysis of the effect of medication exposure confirmed the primary findings of better survival in patients who were initially prescribed a long-acting β-agonist (Table 4). Appendix Table 8 provides information on the number of person-years and percentage of total person-years spent receiving a long-acting β-agonist or long-acting anticholinergic in each of the treatment groups in each year of follow-up. It also provides information about medication crossover and inhaled corticosteroid use during the follow-up period. Adherence to the index medication was not optimal in either medication group, and patients commonly received the nonindex medication. Patients who received a long-acting anticholinergic were more adherent and less likely to have received a long-acting β-agonist during the follow-up period than vice versa. They were also less likely to have received an inhaled corticosteroid.
The validated case definition of COPD based on health administrative data had a positive predictive value of 0.86 when applied to patients aged 65 years or older (9). This means that an estimated 14% of those included in our analysis may not have had COPD. The inclusion of misclassified patients in the cohort could have led to incorrect results in 2 ways. First, the misclassified patients could have been more (or less) healthy than those correctly identified and could have been concentrated in 1 of the 2 treatment groups, thus contributing to better (or worse) outcomes in that group. Second, misclassification could have resulted in an apparent increase in the precision of results, thus decreasing the P value and narrowing the CI for the estimated hazard ratios. To determine how each of these might have influenced the results, we estimated the true hazard ratio and its CI under a range of assumptions about the health of patients who were misclassified relative to those who truly had COPD and the effect of misclassification on the precision of the SE.
Appendix Table 9 shows that our results could be explained if misclassification resulted in sufficiently healthier patients in the long-acting β-agonist group (for example, because they had asthma, which commonly has lower mortality than COPD) or sufficiently sicker patients in the long-acting anticholinergic group (for example, because their true disease was not being recognized or treated properly). Under the assumptions that all patients misclassified as having COPD were in the long-acting β-agonist group and that they were 30% less likely to die (1.0 − 0.70 = 0.3, or 30%) than those with true COPD, the true hazard ratio would be 1.04 (CI, 1.00 to 1.09). Although the point estimate for the hazard ratio is still greater than 1.0, the lower bound of the CI is compatible with no drug difference (the P value for the comparison would no longer be statistically significant). Likewise, if all misclassified patients were in the long-acting anticholinergic group and were 30% more likely to die, the lower bound of the CI for the true hazard ratio would be 1.00. The assumption that all misclassified patients are in the same treatment group is conservative because increased inequality in the distribution of the misclassified patients leads to lower true hazard ratios. Finally, placing all patients who were misclassified in the long-acting β-agonist group and assuming a 20% reduction in the risk for death meant that misclassification would have had to decrease the observed SE of the estimate by more than 50% to widen the true CI to include a value of 1.0.
Appendix Table 9.
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Leonardo M. Fabbri
Department of Oncology, Hematology and Respiratory Diseases, University of Modena & Reggio Emilia, M
May 27, 2011
SAFETY OF INHALED LONG-ACTING ANTICHOLINERGICS
Based on data from health administrative databases in Ontario, Canada, and in contrast to their previous findings (1), Gershon et al (2) describe an increase in mortality and hospitalization in chronic obstructive pulmonary disease (COPD) patients aged 66 years or older receiving the long-acting anticholinergic tiotropium as a first prescription compared with patients starting with long-acting beta- agonists (LABAs). Acknowledging the inherent limitations of this retrospective database analysis, the authors conclude that "further research is needed to confirm these findings in randomized controlled trials". We would like to note that this suggested further research has already been performed and published in the Prevention Of Exacerbations with Tiotropium in COPD (POET) study (3), a randomized, controlled, double- blind trial directly comparing tiotropium with the LABA salmeterol for one year. This trial is the largest head-to-head comparison of these two therapeutic regimens comprising approximately 7400 patients with COPD. The POET study (3) showed that tiotropium was significantly more effective than salmeterol in all assessed COPD exacerbation endpoints. In addition, the incidence of serious adverse events, and of adverse events leading to the discontinuation of treatment, was shown to be similar in the two treatment arms, and outcomes were consistent across age and COPD severity groups and concomitant medication. Specifically, all-cause mortality (vital status follow-up to day 360, 99.1% complete) was not significantly different between tiotropium (64 deaths [1.7%]) and salmeterol (78 deaths [2.1%]). This was independent of sub-group according to age, and including patients aged >65 years. In a pre-specified sub-group analysis, the hazard ratio (HR) for all-cause mortality was numerically in favor of tiotropium (HR, 0.84, 95% confidence interval [CI], 0.47-1.51 for patients aged between 65 and <75 years; HR, 0.78, 95% CI, 0.39-1.59 for patients aged 75 years or more) (4). This is another example illustrating that observations of associations in retrospective cohort studies are not necessarily confirmed in randomized controlled trials, which remain the gold standard for proving causality (5).
1. Gershon AS, Wang L, To T, Luo J, Upshur RE. Survival with tiotropium compared to long acting Beta-2-agonists in Chronic Obstructive Pulmonary Disease. COPD. 2008;5:229-34. [PMID: 18671148]
2. Gershon A, Croxford R, To T, Stanbrook MB, Upshur R, Sanchez-Romeu P, et al. Comparison of Inhaled Long-Acting beta-Agonists and Anticholinergic Effectiveness in Older Patients with Chronic Obstructive Pulmonary Disease: A Cohort Study. Ann Intern Med. 2011;154:583-92. [PMID: 21536937]
3. Vogelmeier C, Hederer B, Glaab T, Schmidt H, Rutten-van M?lken MP, Beeh KM, et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med. 2011;364:1093-103. [PMID: 21428765]
4. Boehringer Ingelheim, data on file.
5. Drummond MB, Dasenbrook EC, Pitz MW, Murphy DJ, Fan E. Inhaled corticosteroids in patients with stable chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA. 2008;300:2407-16. Erratum in: JAMA. 2009;301:1024. [PMID: 19033591]
Dr Vogelmeier has received consulting fees/honoraria and support for travel to meetings from Boehringer Ingelheim; is a board member for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Mundipharma, Novartis and Nycomed; and has received fees for expert testimony and grants from Talecris and payment for lectures/speaking from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Janssen-Cilag, Merck Sharp & Dohme, Novartis, Nycomed, and Talecris. Dr Rabe has received consultancy fees and honoraria from, and is a board member for, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Nycomed, Pfizer; and has received grants from Altana, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Roche. Dr Fabbri has received consultancy fees from Actelion, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Elevation Pharmaceuticals, Merck Sharp & Dohme, Novartis, Nycomed, Pearl Therapeutics, Roche and Sigma-Tau; payment for lectures and support for travel expenses from AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Euromediform SrL, GlaxoSmithKline, German Centre for Lung Research, Merck Sharp & Dohme,Menarini, Mundipharma International, Novartis, Nycomed, TEVA Pharmaceuticals, Pfizer, and Sigma-Tau; and LMF's institution has received grants from Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Italian Ministry of Health, Italian Ministry for University and Research, Merck Sharp & Dohme, Nycomed, and Sigma-Tau.
Hitachinaka Education and Research Center, The University of Tsukuba
June 29, 2011
Older adults initially prescribed LABA, but not long-acting anticholinergics, may be asthmatic rather than pure COPD patients
It has been recently reported that long-acting inhaled ?-agonists (LABA) for the management of moderate COPD seem to have lower mortality than those initially prescribed long-acting anticholinergics in older adults with COPD(1). The study is sensational, but may be wrong. First. Elderly COPD is very complex. Pure COPD without asthmatic component airways in older adults are fairly difficult to be diagnosed by general physicians (2). The definition of the COPD, asthma, COPD with asthma, and COPD with heart failure is very poorly written in the study. Second. COPD mortality is considerably affected by age and acute exacerbation history (3). The initially prescribed long-acting anticholinergics groups have a significantly greater rate of acute exacerbation number, indicating that these patients are prone to acute exacerbators among COPD patients. Third. We always think the LABA prescription for wheeze asthmatic rather than dry cough type COPD initially (4). That is why the LABA prisrcctors may somehow imply the COPD patients with asthmatic domain. Importantly, the mortality is greater in asthma patients rather than COPD patients. Thus, the results of the current study may be just based on the therapeutic/diagnostic decision bias between asthma and COPD. The results may not be associated with agent superiority for the mortally on COPD itself. The bias is likely to be introduced in many trials on widely prescribed treatments in patients with chronic disease (5). Furthermore, elderly patients with COPD have an increased risk of systemic events including heart attacks, bone fractures, and depression. A multidisciplinary approach for the systemic complication, not just for airway bronchodilators, may determine the prognosis of the older COPD patients.
1) Gershon A, Croxford R, To T, Stanbrook MB, Upshur R, Sanchez-Romeu P, Stukel T. Comparison of inhaled long-acting ?-agonist and anticholinergic effectiveness in older patients with chronic obstructive pulmonary disease: a cohort study. Ann Intern Med. 2011 May 3;154(9):583-92. PMID:21536937
2) McDonald VM, Higgins I, Simpson JL, Gibson PG. The importance of clinical management problems in older people with COPD and asthma: do patients and physicians agree? Prim Care Respir J. 2011 Mar 29. pii: pcrj- 2009-12-0100-R3. doi: 10.4104/pcrj.2011.00025. [Epub ahead of print] PMID:21448550
3) Hurst JR, Vestbo J, Anzueto A, Locantore N, M?llerova H, Tal-Singer R, Miller B, Lomas DA, Agusti A, Macnee W, Calverley P, Rennard S, Wouters EF, Wedzicha JA; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363(12):1128-38. PMID:20843247
4) Gooneratne NS, Patel NP, Corcoran A. Chronic obstructive pulmonary disease diagnosis and management in older adults. J Am Geriatr Soc. 2010 Jun;58(6):1153-62.
5) Vollenweider D, Boyd CM, Puhan MA. High prevalence of potential biases threatens the interpretation of trials in patients with chronic disease. BMC Med. 2011 Jun 13;9(1):73. [Epub ahead of print]
Matthew B. Stanbrook
Institute for Clinical Evaluative Sciences in Ontario, University of Toronto
September 7, 2011
Author's response to Fabbri, et al.
To The Editor:
We thank Fabbri et al. for their comments and congratulate them on successfully conducting the POET-COPD study,(1) which was published when our paper was in press. While POET-COPD adds valuable new evidence to our understanding of the comparative efficacy of long-acting bronchodilators in COPD, it is important to recognize that its findings do not necessarily contradict the findings of our paper because of key differences between the two studies--most notably differences in study population, design, and outcomes.
The most salient difference is in study populations. The POET-COPD study, like virtually all such randomized trials in COPD but unlike our study, excluded patients with congestive heart failure, arrhythmias, and recent MI,(1) who may be the very individuals most at risk for adverse events. Also, while our study observed patients from the time of their first use of a long-acting bronchodilator, a majority of patients in POET- COPD were already receiving a long-acting bronchodilator at baseline. By virtue of the fact that they tolerated their regimen and volunteered to take it in a study, this group was more likely to have favorable outcomes. A treatment-naive subgroup of POET-COPD patients was reported to be similar to the overall cohort with respect to exacerbations, but mortality in this subgroup was not reported.(1)
A second difference is that participants in the POET-COPD study who were randomized to tiotropium were precluded from adding or switching to a long-acting beta-agonist, and vice versa,(1) while in our study there was no such restriction. In real-life practice, such switches and additions happen routinely, in keeping with recommendations of current COPD guidelines.(2) Therefore, while the findings of POET-COPD study may apply to specific clinical situations, our study is likely more representative of what usually happens in actual clinical practice.
Lastly, mortality was the primary outcome in our study, while in POET -COPD the primary outcome was exacerbations. POET-COPD was not adequately powered to find small differences in mortality, having enrolled 7376 patients in contrast to the 46,403 patients included in our study.
We agree with Fabbri et al. that a randomized trial provides the highest level of evidence for causal associations, but observational research often plays an essential role in identifying unintended consequences of therapy that may differ in actual practice from findings observed in the idealized context of a randomized trial.(3) We remain concerned that, in current clinical practice, the choice of initial long- acting bronchodilator therapy may lead to different outcomes, including mortality. The POET-COPD study does not fully allay these concerns for the reasons described above. We think that to confirm or refute our findings would instead require a pragmatic randomized trial in which patients were assigned to either class of long-acting bronchodilator (and ideally also a group assigned to both) and allowed to add or cross over to other therapies without restriction. However, we anticipate that such a trial would be very large and expensive, which would present substantial feasibility barriers.
Matthew B. Stanbrook, MD PHD
Andrea Gershon, MD, MSc Institute for Clinical Evaluative Sciences in Ontario University of Toronto
1. Vogelmeier C, Hederer B, Glaab T, et al. for the POET-COPD Investigators. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med 2011;364:1093-1103.
2. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2010. Available from: http://www.goldcopd.org/.
3. Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004;351:543-51.
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