Todd A. Lee, PharmD, PhD; A. Simon Pickard, PhD; David H. Au, MD, MS; Brian Bartle, MPH; Kevin B. Weiss, MD, MPH, MS
Note: At the time of this work, Dr. Weiss was at the Center for Management of Complex Chronic Care, Hines Veterans Affairs Hospital, and the Institute for Healthcare Studies, Northwestern University Feinberg School of Medicine. He has since moved to the American Board of Medical Specialties.
Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the U.S. Department of Veterans Affairs.
Grant Support: By the U.S. Department of Veterans Affairs Health Services Research and Development (IIR 03-307).
Potential Financial Conflicts of Interest:Honoraria: T.A. Lee (AstraZeneca, Novartis), D.H. Au (GlaxoSmithKline). Consultancies: K.B. Weiss (Merck & Co.). Stock ownership or options (other than mutual funds): D.H. Au (Pfizer). Grants received: T.A. Lee (Altana, Aventis, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Merck & Co., Novartis, Pfizer, Schering-Plough, Sepracor, University of Kentucky). Other: D.H. Au (Assessing the Impact of Recent Updates for Advair and Serevent Special Issues Board).
Reproducible Research Statement:Study protocol and data set: Not available. Statistical code: Available from Dr. Lee (email@example.com).
Requests for Single Reprints: Todd A. Lee, PharmD, PhD, Hines Veterans Affairs Hospital, 5000 South 5th Avenue (151-H), Hines, IL 60141; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Lee and Mr. Bartle: Hines Veterans Affairs Hospital, 5000 South 5th Avenue (151-H), Hines, IL 60141.
Dr. Pickard: 833 South Wood Street, RM164 MC886, Chicago, IL 60612.
Dr. Au: Veterans Affairs Puget Sound Health Care System, Health Services Research and Development (152), 1660 South Columbian Way, Seattle, WA 98108.
Dr. Weiss: American Board of Medical Specialties, 1007 Church Street, Suite 404, Evanston, IL 60201-5913.
Author Contributions: Conception and design: T.A. Lee, D.H. Au, K.B. Weiss.
Analysis and interpretation of the data: T.A. Lee, A.S. Pickard, D.H. Au, B. Bartle, K.B. Weiss.
Drafting of the article: T.A. Lee, A.S. Pickard, D.H. Au, K.B. Weiss.
Critical revision of the article for important intellectual content: T.A. Lee, A.S. Pickard, D.H. Au, B. Bartle, K.B. Weiss.
Final approval of the article: T.A. Lee, A.S. Pickard, D.H. Au, B. Bartle, K.B. Weiss.
Statistical expertise: T.A. Lee, A.S. Pickard.
Obtaining of funding: T.A. Lee.
Administrative, technical, or logistic support: B. Bartle.
Collection and assembly of data: A.S. Pickard, B. Bartle.
Lee TA, Pickard AS, Au DH, Bartle B, Weiss KB. Risk for Death Associated with Medications for Recently Diagnosed Chronic Obstructive Pulmonary Disease. Ann Intern Med. 2008;149:380-390. doi: 10.7326/0003-4819-149-6-200809160-00004
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Published: Ann Intern Med. 2008;149(6):380-390.
Many think we need more information about the safety of respiratory medications for chronic obstructive pulmonary disease (COPD).
This large case–control study examined associations between medications and risk for death in veterans with newly diagnosed COPD. Inhaled corticosteroids were associated with decreased risk for death. Theophylline and ipratropium were associated with increased risk for respiratory and cardiovascular death, respectively.
Potential confounders, such as smoking status and disease severity, were not known. Associations may not reflect causal relationships.
Additional research about the safety of ipratropium, one of the most commonly prescribed medications for COPD, is needed.
Chronic obstructive pulmonary disease (COPD) is associated with substantial burden in terms of prevalence of disease (1), death and disability risk (2, 3), and health care costs (4). Despite recent interest in examining long-term outcomes associated with medications in patients with COPD (5, 6), some issues are not easily addressed by using randomized clinical trials. From a pharmacovigilance perspective, relatively rare adverse events—such as death associated with medication use—may not be detected in the short term. The patients who receive a medication may not be similar to those participating in clinical trials (7, 8) and may be more vulnerable to such events. Thus, evidence of longer-term benefits and harms associated with medications—particularly in patients with COPD, who tend to be elderly and have multiple comorbid conditions (9)—can be informed by research that relies on observational data.
Potential safety concerns with medications used to manage COPD may be substantial. A recent meta-analysis (10) showed a nearly 2.5-fold increase in respiratory deaths among patients receiving long-acting β-agonists compared with those receiving placebo. In the Lung Health Study (11), the group randomly assigned to ipratropium bromide had more than twice as many cardiovascular deaths as those receiving placebo. In addition, the U.S. Food and Drug Administration recently issued a notice regarding the potential for an increased risk for stroke associated with tiotropium use in patients with COPD (12). The extent to which these safety concerns exist and can be generalized to patients with COPD outside the context of clinical trials is unclear. Therefore, we sought to examine the association between medication use and risk for death, including respiratory and cardiovascular deaths, in a large population of patients with recently diagnosed COPD.
We conducted this nested case–control study in patients with recently diagnosed COPD by using national Veterans Affairs inpatient, outpatient, pharmacy, and mortality databases, supplemented with data from the Centers for Medicare & Medicaid Services. Our sample comprised U.S. veterans who used the U.S. Veterans Health Administration health care system. The Hines Veterans Affairs Hospital, Hines, Illinois, institutional review board approved our research.
Patients were eligible for inclusion if they received a diagnosis of COPD (International Classification of Diseases, 9th Revision [ICD-9], codes 491.x, 492.x, or 496) between 1 October 1999 and 30 September 2003 at 2 or more outpatient visits within 12 months or were admitted to the hospital with a primary diagnosis of COPD. Patients had to be 45 years of age or older when they received their first eligible diagnosis, have used Veterans Health Administration health care services for at least 1 year before their first COPD diagnosis, and have received respiratory medications. We excluded patients with a diagnosis of asthma. We followed patients from the date of their second eligible outpatient visit or their inpatient visit until death or 30 September 2004.
We identified all deaths that occurred during follow-up by using the Veterans Affairs Vital Status database, a combination of Veterans Affairs, Medicare, and Social Security Administration mortality data that captures approximately 98% of veteran deaths (13). Of these, 40% was randomly sampled and we attempted to determine cause of death. This sample was estimated to provide more than 80% power to detect odds ratios of 0.85 or lower or 1.15 or higher for each medication class. We ascertained cause of death by using National Death Index Plus data from the National Center for Health Statistics. We defined 4 groups of case patients on the basis of cause of death: respiratory, cardiovascular, respiratory or cardiovascular, and all-cause mortality. We defined respiratory as death due to a respiratory system disease (ICD-10 codes J00 to J99) and cardiovascular as death due to ischemic heart disease (ICD-10 codes I20 to I25), cardiomyopathy, cardiac arrest, or arrhythmias (ICD-10 codes I42 to I51). The index date for case patients was their death date.
Selecting more than 5 control participants per case patient can yield limited gains in efficiency; however, because we were assessing several medications simultaneously, we selected up to 10 control participants per case patient (14). We randomly selected control participants for each case patient from eligible patients who were alive at the time of the case event (15, 16). We matched control participants to case patients individually on the basis of sex, age category (45 to 54 years, 55 to 64 years, 65 to 74 years, 75 to 84 years, and ≥85 years of age), region of the country, and year of diagnosis. We assigned control participants the same index date as their matched case patients.
We defined exposure to respiratory medications as having received medications in the 180 days preceding each patient's index date. We identified medication exposure to inhaled corticosteroids, ipratropium, long-acting β-agonists, theophylline, and short-acting β-agonists. We defined primary exposure as any exposure in the 180-day period before the index date. We created mutually exclusive medication regimens on the basis of medication exposure. Exposure to short-acting β-agonists was not considered as part of the regimen but was included as a covariate in the analysis.
We identified covariates by using data from the year before diagnosis date until the index date. We used pharmacy data to identify medication use, including exposure to systemic steroids, antihypertensives, lipid-lowering medications, antiarrhythmics, and diabetes medications. We used inpatient and outpatient diagnoses to identify comorbid conditions. We measured health care utilization as the annual number of hospitalizations and outpatient physician visits. We identified COPD exacerbations during follow-up and whether they were inpatient or outpatient by using a previously described algorithm (17).
We performed separate analyses for respiratory-specific, cardiovascular-specific, and all-cause mortality. We used conditional logistic regression to estimate adjusted odds ratios (ORs) and 95% CIs. We included the variables that we considered clinically important in each of the regression models. Specifically, we included measures of COPD-related severity in all of the models and included markers of cardiovascular disease in the models for cardiovascular and all-cause mortality. We included any remaining variables that changed OR estimates for respiratory medications by more than 10% in the final models (18). We assessed model fit by using the Bayesian information criterion and the Wald test of likelihood ratios and through examination of outlier effects with leverage and fit diagnostics (19). Adjusted odds ratios represented risk for events in patients receiving medication compared with those who had not received inhaled corticosteroids, ipratropium, long-acting β-agonists, or theophylline in the previous 6 months. We performed all analyses with Stata/MP 10.0 for Windows (StataCorp, College Station, Texas).
We conducted several sensitivity analyses to evaluate the robustness of our results. First, we restricted the comparison group to patients who were actively treated with a short-acting β-agonist in the 180 days preceding the index date. Second, because veterans may use health care services outside the Veterans Health Administration system, we restricted the analysis to patients 65 years of age or older. We used Medicare health care utilization data on these patients to capture health care utilization outside of the Veterans Health Administration system. Third, we examined dose response by classifying those in the highest quartile of average daily dose into a high-dose group and the rest of those exposed into a low-dose group. Fourth, to observe the effects of ipratropium independent of short-acting β-agonist exposure, we excluded patients who received a combination of ipratropium and short-acting β-agonists in a single inhaler. Fifth, to address the imbalance in prevalence of chronic heart failure between case patients and control participants, we created analytic cohorts by matching on presence of chronic heart failure and repeated our analyses. Finally, we used the array approach to estimate the effect that unmeasured confounding could have had on point estimates of the association between medications and mortality (20). We varied the level of risk associated with the unmeasured confounder and the prevalence in the medication groups relative to the no-treatment groups to determine what level of differential exposure would change the conclusions from the primary analysis. We focused on current smoking rates and COPD severity because we considered these to be 2 of the most important and influential unmeasured confounders. We compared rates of smoking status and COPD severity across treatment groups by using data from a recently published study (21).
This research was funded by the U.S. Department of Veterans Affairs Health Services Research and Development. The funding source had no role in the design, analysis, interpretation, or reporting of results or in the decision to submit the manuscript for publication.
We identified 145 020 patients who met inclusion criteria; of whom, 32 130 died (Figure 1). We located cause-of-death data for 11 897 patients but could not match data for 955 potential case patients. Of the patients for whom cause-of-death data were available, 2405 deaths were respiratory and 3159 were cardiovascular. Within the respiratory mortality analysis, case patients had lower rates of hypertension and osteoarthritis, higher rates of chronic heart failure, and more COPD exacerbations (Table 1). Among those included in the cardiovascular mortality analysis, case patients had higher rates of cardiovascular comorbid conditions and COPD exacerbations, which suggests more severe respiratory disease. Case patients had a similar or higher prevalence of respiratory medication use than control participants (Table 2). The 3 top regimens for each group were no medication or short-acting β-agonists only, ipratropium only, and inhaled corticosteroids and ipratropium.
COPD = chronic obstructive pulmonary disease.
After we adjusted for differences in covariates, both inhaled corticosteroids and long-acting β-agonists were associated with reduced odds of death (OR, 0.80 [95% CI, 0.78 to 0.83] for inhaled corticosteroids and 0.92 [CI, 0.88 to 0.96] for long-acting β-agonists), whereas ipratropium was associated with an increased risk (OR, 1.11 [CI, 1.08 to 1.15]). For cause-specific mortality, theophylline exposure was associated with a statistically significant increase in respiratory deaths compared with the unexposed group (OR, 1.71 [CI, 1.46 to 2.00]) (Table 3). Although point estimates indicated a more than 10% increase in the odds of respiratory death associated with long-acting β-agonists (OR, 1.12 [CI, 0.97 to 1.30]) and a more than 10% decrease with inhaled corticosteroids (OR, 0.88 [CI, 0.79 to 1.00]), neither was statistically significant. With respect to cardiovascular death, ipratropium exposure was associated with a 34% increase in the odds of cardiovascular death (OR, 1.34 [CI, 1.22 to 1.47]), whereas inhaled corticosteroid exposure was associated with a 20% decrease in the odds of a cardiovascular death (OR, 0.80 [CI, 0.72 to 0.88]). Long-acting β-agonists (OR, 0.97 [CI, 0.84 to 1.11]) and theophylline (OR, 1.16 [CI, 0.99 to 1.37]) were not associated with statistically significant risks in cardiovascular deaths.
We found estimates of similar magnitude across the sensitivity analyses of patient subgroups for each outcome (Figure 2). In the sensitivity analysis based on dose of medication, we found higher doses to be associated with a larger effect than lower doses, consistent with a dose response to the medication.
Bars indicate 95% CIs. CHF = chronic heart failure; ICS = inhaled corticosteroid; IPRA = ipratropium; LABA = long-acting β-agonist; SABA = short-acting β-agonist; THEO = theophylline.
A recently published study of veterans (21) reported the prevalence of current smokers to be 11% among those receiving short-acting β-agonists or not treated, 20% among those receiving ipratropium, 18% among those receiving inhaled corticosteroids, and 16% among those receiving long-acting β-agonists. With current smoking associated with a relative risk for death of 1.5 (22), these estimates would result in adjusted risk ratios of 0.77 for inhaled corticosteroids, 1.08 for ipratropium, and 0.90 for long-acting β-agonists. To reduce the association between ipratropium and all-cause mortality to an adjusted OR of 1.0, the proportion of current smokers in the ipratropium-treated group would have to reach 35% relative to the 11% observed in the no-treatment group. To reduce the association between cardiovascular death and ipratropium to an odds ratio of 1.0, the prevalence of current smoking in the ipratropium group would have had to be at least 80%.
For COPD disease severity, we assumed an increase of 1.4 in the risk for death for those with moderate to severe COPD relative to those with mild COPD, based on the NHANES (National Health and Nutrition Examination Surveys) data in Maninno and colleagues' study (23). From the published pilot study, we found the prevalence of moderate to severe COPD to be approximately 20% in the untreated group; 45% to 55% in those receiving inhaled corticosteroids, ipratropium, or long-acting β-agonists; and 70% in those treated for COPD. However, COPD was not newly diagnosed in the patients in this study, and the differential estimates are therefore probably higher than those for patients with newly diagnosed COPD (21). Accounting for severity as an unmeasured confounder would result in an all-cause mortality risk ratio of 0.90 for theophylline, 1.02 for ipratropium, 0.72 for inhaled corticosteroids, and 0.83 for long-acting β-agonists. For respiratory death, if the estimated risk for COPD-related death is increased nearly 4-fold in those with moderate to severe disease compared with those with mild disease, the risk associated with theophylline would be reduced to 0.88 if the prevalence of moderate to severe disease was 70% in the theophylline group and 20% in the no-treatment group.
Among medication regimens, those that included theophylline were associated with increased risk for respiratory death. For cardiovascular death, ipratropium alone (OR, 1.42 [CI, 1.27 to 1.59]) and ipratropium plus theophylline (OR, 1.47 [CI, 1.09 to 1.98]) were associated with increased risk, whereas the presence of inhaled corticosteroids with ipratropium reduced the risk for cardiovascular death (OR, 1.04 [CI, 0.90 to 1.22]; P < 0.001 for Wald test compared with ipratropium alone). In the all-cause mortality group, inhaled corticosteroids were consistently associated with reduced odds of death when used alone or in combination with other medications, whereas ipratropium and ipratropium plus theophylline were associated with elevated risk for death.
We found limited evidence on the mortality-related benefits and harms of COPD-related medications, largely because such events require longer-term follow-up and more individuals than are found in clinical trials of COPD. For this reason, we conducted a nested case–control study to examine the association between COPD medications and respiratory- and cardiovascular-specific deaths. Inhaled corticosteroids and long-acting β-agonists were associated with a reduction in the odds of all-cause mortality compared with no treatment or short-acting β-agonists alone. Ipratropium was associated with an 11% increase in the risk for death.
Several recent publications (5, 10, 24–32) have focused on medication use and mortality in patients with COPD. Two recent randomized, controlled trials, the TORCH (Towards a Revolution in COPD Health) trial (5) and the INSPIRE (Investigating New Standards for Prophylaxis in Reducing Exacerbations) study (32), showed reduced risk for death in patients treated with inhaled corticosteroids and long-acting β-agonists. The TORCH trial reported a hazard ratio for all-cause mortality of 0.83 (CI, 0.68 to 1.00) among patients who received inhaled corticosteroids plus long-acting β-agonists compared with those who received placebo, which is similar to the 0.80 reduction in risk that we observed for inhaled corticosteroids and the 0.78 reduction for the combination of inhaled corticosteroids and long-acting β-agonists (5). These findings are consistent with meta-analyses that showed a reduced mortality risk associated with inhaled corticosteroids (30, 31). Findings on the association between ipratropium and mortality have been less consistent. Ringbaek and Viskum (27) found an increased risk for all-cause mortality associated with ipratropium use (relative risk, 1.6 [CI, 1.2 to 2.1]) that is similar to our results, whereas Sin and Tu (29) found no association between ipratropium use and all-cause mortality (relative risk, 1.03 [CI, 0.98 to 1.08]).
We found statistically significant and clinically meaningful associations between cause-specific deaths and medication use among patients with recently diagnosed COPD compared with patients receiving short-acting β-agonists or no medication. Theophylline was associated with an increased risk for respiratory death, ipratropium with an increased risk for cardiovascular death, and inhaled corticosteroids with a 20% reduction in the odds of cardiovascular death and a 15% reduction in the odds of either cardiovascular or respiratory death. Given the extensive use of ipratropium in patients with COPD, our data suggest an increased risk for cardiovascular death with ipratropium that could amount to a substantial number of premature deaths in patients with COPD.
The increased risk for cardiovascular death associated with ipratropium that we observed is consistent with reports from the Lung Health Study (11), a 5-year, 3-group, randomized, controlled trial that compared smoking cessation plus ipratropium, smoking cessation plus placebo, and usual care and found a more than a 2-fold difference in cardiovascular deaths between the ipratropium group and the placebo group (18 deaths vs. 7 deaths; P = 0.027, log-rank test). Of note, the investigators believed that the mortality effect they observed may have been a false-positive result from multiple comparisons.
Our results raise concerns about the safety of ipratropium, one of the most commonly prescribed medications in patients with COPD. Our finding of an increased risk for cardiovascular death, consistent with results from the Lung Health Study, raises concerns about a potential harm associated with ipratropium rather than simply a lack of effectiveness, which could contribute to a higher overall mortality rate. Prescribing information for ipratropium does not include information on the potential risk for cardiovascular death; it is therefore unlikely that providers and patients are aware of the potential risks associated with ipratropium use that should be weighed against its benefits. Attention to safety and effectiveness issues in the broader class of anticholinergic medications is also warranted. Tiotropium, a longer-acting anticholinergic medication for patients with COPD, carries an unclear risk for cardiovascular events; in addition, a recent notice from the U.S. Food and Drug Administration (12) reports a potential increased risk for stroke.
In addition to the risk for cardiovascular death with ipratropium, we found an increased risk for cardiovascular or respiratory death in patients exposed to theophylline that was primarily due to increased respiratory deaths. Despite limited evidence on the value of theophylline for treating patients with COPD, nearly 10% of patients received the drug. Although we attempted to control for differences in disease severity by limiting the cohort to patients with recently diagnosed COPD and by adjusting for COPD exacerbations, some of the increased risk associated with theophylline may be due to more severe disease in patients exposed to theophylline. We therefore conducted a sensitivity analysis to evaluate the influence of disease severity as an unmeasured confounder on disease outcomes. We found that the observed association between theophylline and respiratory mortality could be completely explained by differences in disease severity between the groups if the prevalence of moderate to severe disease was 60% in the theophylline-treated patients relative to 20% in the comparison group. This was less than the 70% prevalence of moderate to severe disease that we observed among our small cohort of patients with COPD who received theophylline; however, this group was not restricted to patients with newly diagnosed COPD. Therefore, differences in disease severity may account for some of the observed difference in risk for respiratory death associated with theophylline; however, it is unclear whether a large enough difference in severity would exist among those with newly diagnosed COPD to fully explain our findings.
In contrast, we found inhaled corticosteroid use was associated with decreased risk for cardiovascular death. Our estimate of a 22% reduction in the risk for cardiovascular death, combined cardiovascular and respiratory death, and all-cause mortality in patients exposed to inhaled corticosteroids and long-acting β-agonists is consistent with the hazard ratio of 0.78 (CI, 0.57 to 1.06) reported by the TORCH trial for COPD-related deaths (5). Our results suggest that decreased risk for cardiovascular events may be responsible for benefits associated with inhaled corticosteroids in patients with recently diagnosed COPD. Previous reports (33) have shown that inhaled corticosteroids reduce inflammatory markers in patients with COPD; a hypothesized mechanism includes potential reduction in cardiovascular risk. However, these results need to be considered in the context of other cause-specific mortality estimates. The patient-level meta-analysis that found benefit versus all-cause mortality (31) found no association between inhaled corticosteroids and cardiovascular death (hazard ratio, 0.98 [CI, 0.59 to 1.62]), although the study was inadequately powered to address this outcome. Of note, the TORCH trial (5), the INSPIRE study (32), and a recently published observational study (34) have all found an increased risk for pneumonia associated with use of inhaled corticosteroids. We did not assess the risk for pneumonia in this cohort, although it needs to be considered in relation to the mortality findings by patients and providers when making treatment decisions.
Our study has limitations. Observational studies are susceptible to bias due to confounding by indication, in which patients with more severe disease may be more likely to have events and therefore are more likely to be exposed to the treatment of interest. We attempted to minimize concerns about this effect by focusing on recently diagnosed disease and by controlling for markers of disease severity. In addition, we conducted a sensitivity analysis to examine the potential effect of unmeasured confounding due to disease severity. In a small sample of veterans with COPD (21), we found a substantial difference in the proportion of patients with moderate to severe COPD between those who received only short-acting β-agonists or no treatment and those who received other treatments. If this difference in severity was present in our study, it would have been sufficient to explain the observed increase in risk for respiratory death associated with theophylline. Severity of COPD as an unmeasured confounder could have also reduced the association between ipratropium and all-cause mortality to 1.02. However, this cohort included patients with prevalent COPD and probably overestimates the difference in the prevalence of severity by treatment group. We found that for unmeasured severity to fully account for the observed differences, the prevalence of severe disease in patients treated with theophylline would have to be 3 times that observed in those who received no treatment or who received only short-acting β-agonists. For the association between all-cause mortality and ipratropium, the prevalence of severe disease in the ipratropium group would need to be nearly 2.5 times that observed in the patients who received no treatment or who only received short-acting β-agonists. Thus, differences in severity between treatment groups would need to be very large to account for the associations that we observed.
Similar to disease severity, we could not ascertain smoking status among our cohort, which may have introduced unmeasured confounding. However, it is probable that many of these patients have a history of substantial smoking, given the clinical diagnosis of COPD. Our sensitivity analysis of current smoking rates indicates that current smokers would have to account for a larger proportion of those treated with ipratropium to reduce the odds ratio to 1.0 for either all-cause mortality or cardiovascular death. We also conducted several other sensitivity analyses that strengthen our findings due to the consistency of the results. We found consistent results across the subgroups of patients for each of the analyses.
Our study is probably underpowered for many of the medications examined in the regimen-based analysis of cause-specific mortality. Because of the low rates of exposure to some regimens, we are unlikely to find statistically significant differences. However, for the most commonly used medications, we found risks consistent with the main effects observed for each medication. We also found that combinations of medications may reduce the risks associated with individual medication exposures. In addition, many of the point estimates for the regimen-based analyses of cause-specific mortality were consistent with the all-cause mortality analysis, in which the larger number of included case patients alleviated problems of statistical power.
Our results are most applicable to men with recently diagnosed COPD and may not apply to patients with more severe disease or to women. We used National Death Index Plus data to identify cause of death, which has shown high concordance with coding by trained nosologists but may not be consistent with adjudicated deaths in clinical trials (35, 36). The TORCH trial investigators observed 52% agreement between adjudicated deaths and the site investigator's coding of primary cause of death, and agreement increased to 67% compared with either primary or secondary cause listed by the site investigator (37). How adjudicated deaths would relate to underlying cause defined in National Death Index Plus data is unclear and thus it is difficult to know how often the cause of death we identified by using death certificate data would differ from that ascertained by an adjudication committee. The degree of misclassification may be related to severity—patients with more severe disease were more likely to have COPD listed as a cause of death (38). This may raise concerns that individuals treated with ipratropium had less severe disease than other patients and were more likely to be classified as having a non–COPD-related cause of death. However, we also evaluated the association between medication exposure and all-cause mortality. If the relationship between ipratropium and cardiovascular death occurred because deaths were more likely to be classified as cardiovascular than respiratory in the ipratropium group owing to differences in disease severity rather than to medication exposure, we would expect to find no association between ipratropium and all-cause mortality. However, we found an association between ipratropium and all-cause mortality, which warrants concerns about the safety of the medication in treating COPD.
Our study contributes important new evidence on the potential harms associated with medications used in COPD. Ipratropium may increase the risk for cardiovascular death; however, this risk may be attenuated by the concomitant use of inhaled corticosteroids, which were associated with reduction in the risk for all-cause and cardiovascular death. The risk for death due to some medications must be weighed against potential benefits of these medications that are not captured in observational database studies, such as symptom relief, health status, or quality of life. It is not clear, however, that these benefits would outweigh the increased risk for death. Given the risk observed in our study and in previous studies of ipratropium, caution is warranted in the use of ipratropium alone in patients with recently diagnosed COPD. It is also important to further examine this relationship through measurement of cardiovascular events and to measure the effect of such factors as disease severity and smoking status.
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Asakura Medical Association Hospital
September 19, 2008
A potential bias
It is interesting to note that patients taking inhaled corticosteroid (ICS) have reduced mortality in comparison with those taking other types of medication in patients with chronic obstructive pulmonary disease. However, before we start discussion about the direct association of the pharmacological effect of ICS with the reduced mortality, potentially confounding factors to the observation must be considered. Particularly, potential bias in patients deserves attention, as the authors stated. Although the authors proposed a bias in the severity of the disease and smoking status as potential confounders, a potential bias in the sociodemographic distribution among the patients seems to be more relevant to the reduced mortality in patients taking ICS. Although observations in patients with asthma, several studies have suggested that patients with disadvantaged sociodemographic background are less likely to use ICS, either through lower adherence to the treatment (1), or maybe through lower rates of prescription (2). On the other hand, socioeconomic status has been documented to have inverse association with mortality from cardiovascular diseases (3) and other diseases (4). Thus, it is prudent to take these potential confounders into account to adequately appreciate the observed differences in the mortality.
1. Apter AJ, Boston RC, George M, et al. Modifiable barriers to adherence to inhaled steroids among adults with asthma: it's not just black and white. J Allergy Clin Immunol 2003;111(6):1219-26.
2. Kozyrskyj AL, Mustard CA, Simons FE. Socioeconomic status, drug insurance benefits, and new prescriptions for inhaled corticosteroids in schoolchildren with asthma. Arch Pediatr Adolesc Med 2001;155(11):1219 -24.
3. Mackenbach JP, Bos V, Andersen O, et al. Widening socioeconomic inequalities in mortality in six Western European countries. Int J Epidemiol 2003;32(5):830-7.
4. Kunst AE, Groenhof F, Mackenbach JP, Health EW. Occupational class and cause specific mortality in middle aged men in 11 European countries: comparison of population based studies. EU Working Group on Socioeconomic Inequalities in Health. Bmj 1998;316(7145):1636-42.
Nicholas J Gross
Stritch-Loyola School of Medicine
September 24, 2008
Risk of Death Associated with COPD Medications
Despite its very large data base, the study has problems that are inherent in observational data analyses where potential confounding factors cannot be reliably controlled for. Of particular concern in the present study are the absence of data about disease severity and smoking status, as the authors acknowledge. Attempts to adjust for these confounders by reference to a small pilot study of questionable relevance (1) or by internal "measures of disease severity" that are not described in any detail are unreassuring. When the effect size of a treatment of interest, ipratropium versus no ipratropium, is quite small, as here, the inability to adjust with confidence for 2 very weighty confounders throws considerable doubt on the conclusion. Furthermore, after adjustment for covariates the authors calculate the odds ratio for mortality with ipratropium use is reduced to 1.11, which is below the 1.15 threshold of 80% power on which their sample size was calculated.
The inherent methodological problems are probably responsible for a number of other apparent anomalies. I will mention just two. In Table I, the comorbidities hypertension and osteoarthritis appear to be substantially less common in respiratory deaths than case controls; conversely, the use of loop diuretics and digoxin are substantially more common in respiratory deaths. If the odds ratio for each were calculated one might conclude that hypertension and osteoarthritis were protective against, while loop diuretics and digoxin were risk factors for, respiratory death in COPD. Would anyone accept those conclusions?
Secondly in Figure 2, one notes the highest odds ratios for mortality are associated with theophylline usage. But, paradoxically, the risk is seen only in association with respiratory deaths, and not at all with cardiovascular deaths. Theophylline does not have major respiratory side effects. It does, of-course, have serious, sometimes fatal, cardiovascular side effects. How does one make sense of this apparent contradiction?
One is also struck that numerous prospective studies (2) except one very small one (3), have exonerated ipratropium of any associated increase in mortality in COPD, the reverse in fact. The present results could be well explained by disease severity, -a major confounding factor that was not or could not be precisely controlled for. We are left with the uncertainty whether sicker patients received more treatment, or whether the treatment itself contributed to patients' mortality. I suspect the former.
1. Joo MJ, Lee TA, Bartle B, Van de Graaff W, Weiss KB. Patterns of healthcare utilization by COPD severity: a pilot study. Lung 2008;186:307-12
2. Salpeter SR, Buckley NS. Systematic review of clinical outcomes in chronic obstructive pulmonary disease: beta-agonist use compared with anticholinergics and inhaled corticosteroids. Clin Rev Allergy Immunol 2006;31:219-30.
3. Ringbaek T, Viskum K. Is there any association between inhaled ipratropium and mortality in patients with COPD and asthma? Respir Med 2003;97:264-72.
NJG has received payments for consulting with Boehringer-Ingelheim, GlaxoSmithKline, Altana, Almirall, Forest, Dey, and Astra-Zeneca. NJG has received speaking fees from Astra-Zeneca, Boehringer-Ingelheim, Dey, and Pfizer. I have no investments in any Pharmaceutical Company.
Biases in the study of COPD medications on mortality
Lee et al report, using an observational study design, that the use of ipratropium is associated with a 34 % increase in the risk of cardiovascular death and the use of inhaled corticosteroids (ICS) is associated with a 20% reduction in all-cause mortality in COPD patients.(1) Some methodological considerations should be addressed in judging the validity of these findings.
The excess risk of cardiovascular death seen with ipratropium (odds ratio 1.34; 95% CI 1.22-1.47) is possibly due to the marked imbalance in the occurrence of COPD exacerbations during the prior 6 months between cases (64%) and controls (22%).(2) While the data analysis adjusted the odds ratio from 1.75 (crude) to 1.34, the statistical approach did not consider the timing of the exacerbation and was thus unable to distinguish whether the cardiac outcomes occur through the increased likelihood of an exacerbation or whether they require the occurrence of an exacerbation. It is possible that a more refined analysis that can take the timing of exacerbations into account could further reduce the adjusted risk.
The protective effect of inhaled corticosteroids (ICS) on all-cause mortality (odds ratio 0.80; 95% CI 0.78-0.83) contradicts the TORCH randomized controlled trial that found a 6% increase in the death rate (rate ratio 1.06; 95% CI 0.89-1.27) with the ICS fluticasone compared with placebo.(3) Unlike observational studies, the randomized controlled trial design avoids the problem of confounding factors, measured and unmeasured, resulting from imbalances between ICS users and non-users.
The study may also have been subject to immeasurable time bias.(4) In a case-control study of mortality involving a chronic illness such as COPD, hospitalizations just prior to death will be common, so that outpatient prescriptions identified from computerized databases cannot be measured during this hospitalized time period. Thus, hospitalizations before death will lead to an apparently lower use of drugs, while being likely associated with an increased risk of death. This phenomenon will thus create the illusion that the drug is effective at preventing mortality. An illustration of this phenomenon using a cohort of COPD patients showed that fatal cases spent more time in hospital prior to death than controls, so that the odds ratio of death associated with ICS use was 0.60, while a data analysis that accounted for the varying out of hospital measurable times changed this odds ratio to 0.98.(4)
While observational studies are essential to evaluate drug safety, their methods can introduce bias.
(1) Lee TA, Pickard AS, Au DH, Bartle B, Weiss KB. Risk for death associated with medications for recently diagnosed chronic obstructive pulmonary disease. Ann Intern Med. 2008;149:380-390.
(2) Soler-Cataluna JJ, Martinez-Garcia MA, Roman SP, Salcedo E, Navarro M, Ochando R. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax. 2005;60:925-31.
(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) Suissa S. Immeasurable time bias in observational studies of drug effects on mortality. Am J Epidemiol. 2008;168:329-35.
SS and PE have received grants or served on advisory boards for Astra-Zeneca, Boehringer-Ingelheim, GlaxoSmithKline and Sepracor.
Todd A. Lee
Hines VA Hospital, Hines, IL
November 5, 2008
We thank the correspondents for their thoughtful comments. Drs. Suissa and Ernst raise three concerns about our paper. First, to alleviate concerns that the observed risk for ipratropium and cardiovascular mortality was a result of an increased risk of exacerbations in the cases, we conducted an analysis restricted to those without an exacerbation in the 180 days preceding their event date and found a level of risk (OR 1.45, 95% CI 1.14-1.85) similar to the results reported in the article. Second, unmeasured confounding and bias is one possible explanation for discordant results between the TORCH study and our study. Among the other explanations, the difference in outcomes may be related to the patient populations. The population included in our analysis was older, had higher overall and cause-specific mortality rates, was nearly all male, had more co-existing conditions and had differential respiratory medication use prior to entering the study. Third, we were able to measure medications used within the VA healthcare system during inpatient stays and thus the analysis was not subject to concerns about immeasurable time bias.
Dr. Gross raises concerns about observational studies and our ability to adjust for disease severity and smoking status. The inability to measure smoking status was acknowledged in the paper, and the proportion of current smokers in the ipratropium group needed to be nearly 2.5 times higher than in the comparator group to negate the observed association with ipratropium and cardiovascular mortality. COPD exacerbations and hospitalizations were used to characterize disease severity. The observed association with respiratory mortality and theophylline may have been related to residual confounding by severity, given its place in treatment guidelines. However, this is unlikely to be the case with ipratropium as it is used as a first-line medication in the treatment of COPD. The specific hypotheses tested in this study were based on prior research, including a large prospective study of ipratropium that showed an increased risk of cardiovascular hospitalizations and deaths(1). In addition our findings are consistent with a recent meta-analysis that reported similar risks with anticholinergics and cardiovascular outcomes(2).
Finally, the doctor's notes that socioeconomic status may confound the association between medication use and mortality. An advantage of conducting this analysis among US veterans who received care from Veterans Health Administration is the strong emphasis that VA places on equal access to health care that likely minimizes the effects of socioeconomic status compared to other populations.(3,4)
(1) Anthonisen NR, Connett JE, Enright PL, Manfreda J. Hospitalizations and mortality in the Lung Health Study. Am J Respir Crit Care Med. 2002;166:333-39.
(2) Singh S, Loke YK, Furberg CD. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA. 2008;300:1439-50.
(3) Jha AK, Shlipak MG, Hosmer W, Frances CD, Browner WS. Racial differences in mortality among men hospitalized in the Veterans Affairs health care system. JAMA. 2001;285:297-303.
(4) Selim AJ, Fincke G, Berlowitz DR, Cong Z, Miller DR, Ren XS et al. No racial differences in mortality found among Veterans Health Administration out-patients. J Clin Epidemiol. 2004;57:539-42.
Honoraria: T.A. Lee (Astra-Zeneca, Novartis), D.H. Au (GlaxoSmithKline). Stock ownership or options (other than mutual funds): D.H. Au (Pfizer). Grants received: T.A. Lee (Altana, Aventis, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Merck & Co., Novartis, Pfizer, Schering-Plough, Sepracor, University of Kentucky). Other: D.H. Au (Assessing the Impact of Recent Updates for Advair and Serevent Special Issues Board).
Westchester Medical Center, Valhalla, NY 10595
December 3, 2008
Risk for Death Associated with Medications for Recently Diagnosed COPD
To the Editor:
In their pharmacoepidemiology study, Lee and colleagues (1) report the possible association between ipratropium and elevated risk for all-cause and cardiovascular mortality in patients with newly diagnosed chronic obstructive pulmonary disease (COPD). During an Evidence Based Medicine presentation for a group of internal medicine residents we studied this paper with keen interest in research methodologies. The paper refers to a cohort of 145 020 veterans with a new diagnosis of COPD, which excludes those not receiving any respiratory treatment. But all-cause mortality analysis in their study included 320 501 control participants, some of whom obviously would not belong to their cohort. This makes one wonder the source of controls, who are supposed to be patients with COPD who were alive at the end of the study period. If the control group had included patients without COPD, the sensitivity analysis for unmeasured confounders (severity of COPD in this case) would be inaccurate. Also, in table 3, patients not on any respiratory medications or those only on short acting beta-agonists were considered as the reference standard. But as per the study protocol, patients who were not on any respiratory medications were excluded from the study.
We understand that much of medical research is observational and the reporting of observational studies is often of insufficient quality. Thus, we study such research in light of The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies (2). However, this type of fundamental law in the study design would not have been appreciated without an in depth review of the paper.
1. Lee TA, Pickard S, Au DH, Bartle B, Weiss KB. Risk for death associated with medications for recently diagnosed chronic obstructive pulmonary disease. Ann Intern Med. 2008; 149: 380-390.
2. Von Elm E, Altman DG, Egger M, Pocock SJ, GÃ¸tzsche PC, Vandenbroucke JP; STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: Guidelines for Reporting Observational Studies. Ann Intern Med. 2007; 147: 573-577.
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