Chronic obstructive pulmonary disease (COPD) is associated

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1 Article Annals of Internal Medicine Risk for Death Associated with Medications for Recently Diagnosed Chronic Obstructive Pulmonary Disease Todd A. Lee, PharmD, PhD; A. Simon Pickard, PhD; David H. Au, MD, MS; Brian Bartle, MPH; and Kevin B. Weiss, MD, MPH, MS Background: Concerns exist regarding increased risk for mortality associated with some chronic obstructive pulmonary disease (COPD) medications. Objective: To examine the association between various respiratory medications and risk for death in veterans with newly diagnosed COPD. Design: Nested case control study in a cohort identified between 1 October 1999 and 30 September 2003 and followed through 30 September 2004 by using National Veterans Affairs inpatient, outpatient, pharmacy, and mortality databases; Centers for Medicare & Medicaid Services databases; and National Death Index Plus data. Cause of death was ascertained for a random sample of 40% of those who died during follow-up. Case patients were categorized on the basis of all-cause, respiratory, or cardiovascular death. Mortality risk associated with medications was assessed by using conditional logistic regression adjusted for comorbid conditions, health care use, and markers of COPD severity. Setting: U.S. Veterans Health Administration health care system. Measurements: All-cause mortality; respiratory and cardiovascular deaths; and exposure to COPD medications, inhaled corticosteroids, ipratropium, long-acting -agonists, and theophylline in the 6 months preceding death. Results: Adjusted odds ratios (ORs) for all-cause mortality were 0.80 (95% CI, 0.78 to 0.83) for inhaled corticosteroids, 1.11 (CI, 1.08 to 1.15) for ipratropium, 0.92 (CI, 0.88 to 0.96) for longacting -agonists, and 1.05 (CI, 0.99 to 1.10) for theophylline. Ipratropium was associated with increased cardiovascular deaths (OR, 1.34 [CI, 1.22 to 1.47]), whereas inhaled corticosteroids were associated with reduced risk for cardiovascular death (OR, 0.80 [CI, 0.72 to 0.88]). Results were consistent across sensitivity analyses. Limitations: Current smoking status and lung function were not measured. Misclassification of cause-specific mortality is unknown. Conclusion: The possible association between ipratropium and elevated risk for all-cause and cardiovascular death needs further study. : case patients and control participants in the all-cause mortality analysis. Of patients with causeof-death data, 2405 case patients had respiratory deaths and 3159 case patients had cardiovascular deaths. Ann Intern Med. 2008;149: For author affiliations, see end of text. 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 -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. See also: Print Editors Notes Web-Only Conversion of graphics into slides METHODS 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 Admin September 2008 Annals of Internal Medicine Volume 149 Number 6

2 COPD Medications and Mortality Article istration health care system. The Hines Veterans Affairs Hospital, Hines, Illinois, institutional review board approved our research. Cohort 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. 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 Case 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. Exposure We defined exposure to respiratory medications as having received medications in the 180 days preceding Context Many think we need more information about the safety of respiratory medications for chronic obstructive pulmonary disease (COPD). Contribution 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. Caution Potential confounders, such as smoking status and disease severity, were not known. Associations may not reflect causal relationships. Implication Additional research about the safety of ipratropium, one of the most commonly prescribed medications for COPD, is needed. The Editors each patient s index date. We identified medication exposure to inhaled corticosteroids, ipratropium, long-acting -agonists, theophylline, and short-acting -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 -agonists was not considered as part of the regimen but was included as a covariate in the analysis. Covariates 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). Statistical Analysis 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 cardio September 2008 Annals of Internal Medicine Volume 149 Number 6 381

3 Article COPD Medications and Mortality vascular 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 -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 -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 -agonist exposure, we excluded patients who received a combination of ipratropium and short-acting -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). Role of the Funding Source 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. RESULTS We identified patients who met inclusion criteria; of whom, died (Figure 1). We located causeof-death data for 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 -agonists only, ipratropium only, and inhaled corticosteroids and ipratropium. After we adjusted for differences in covariates, both inhaled corticosteroids and long-acting -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 -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 -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 -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. A recently published study of veterans (21) reported the prevalence of current smokers to be 11% among those receiving short-acting -agonists or not treated, 20% among those receiving ipratropium, 18% among those receiving inhaled corticosteroids, and 16% among those receiving long-acting -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 September 2008 Annals of Internal Medicine Volume 149 Number 6

4 COPD Medications and Mortality Article Figure 1. Study flow diagram. Patient with 2 outpatient visits or 1 hospitalization for COPD (n = ) Excluded (n = ) Age <45 y or >100 y: 8401 Recorded date of death before study start date: 234 Recorded date of death before index date: 92 Not receiving respiratory medications: Patient included in cohort (n = ) participants Died during follow-up (n = ) Sample for cause-specific death (n = ) Could not match with cause-ofdeath data (n = 955) Matched with cause-ofdeath data (n = ) participants participants Respiratory death (n = 2405) Cardiovascular death (n = 3159) COPD chronic obstructive pulmonary disease. long-acting -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 ipratropiumtreated 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 -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 16 September 2008 Annals of Internal Medicine Volume 149 Number 6 383

5 Article COPD Medications and Mortality Table 1. Participant Characteristics Characteristic Respiratory Death Cardiovascular Death All-Cause Mortality Case (n 2405) (n ) Case (n 3159) (n ) Case (n ) Men, % Age, % y y y y y Race, % White Black Hispanic Other Unknown Comorbid conditions, % Hypertension Ischemic heart disease Diabetes Osteoarthritis Depression Cancer Chronic heart failure Medications, % Hydrochlorothiazide Loop diuretic Potassium-sparing diuretic Blocker Calcium-channel blocker ACE inhibitor Angiotensin-receptor blocker Antiarrhythmic Digoxin Lipid-lowering medication Insulin Oral hypoglycemic agent Nonsteroidal anti-inflammatory drugs (n ) Annual health care utilization Mean primary care visits (SD), n 3.6 (3.7) 4.1 (3.4) 4.5 (4.1) 4.0 (3.3) 4.2 (3.8) 4.0 (3.4) Mean hospitalizations (SD), n 0.4 (0.7) 0.2 (0.6) 0.6 (1.1) 0.2 (0.6) 0.5 (1.0) 0.3 (0.7) Cumulative COPD exacerbations, % Exacerbation in previous 6 mo, % ACE angiotensin-converting enzyme; COPD chronic obstructive pulmonary disease. 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 -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 September 2008 Annals of Internal Medicine Volume 149 Number 6

6 COPD Medications and Mortality Article (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 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. DISCUSSION 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 -agonists were associated with a reduction in the odds of all-cause mortality compared with no treatment or short-acting -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 -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 -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 -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]). Table 2. Medication Use Related to Chronic Obstructive Pulmonary Disease Regimen Respiratory Death, % Cardiovascular Death, % Respiratory or Cardiovascular Death, % All-Cause Mortality, % Case (n 2405) (n ) Case (n 3159) (n ) Case (n 5564) (n ) Case (n ) Medication use within 6 mo of index date Short-acting -agonists Inhaled corticosteroids Ipratropium Long-acting -agonists Theophylline Medication regimen use within 6 mo of index date None or short-acting agonists only Inhaled corticosteroids Ipratropium Long-acting -agonists Theophylline Inhaled corticosteroids plus ipratropium Inhaled corticosteroids plus long-acting -agonists plus ipratropium Long-acting -agonists plus ipratropium Inhaled corticosteroids plus long-acting -agonists Ipratropium plus theophylline Inhaled corticosteroids plus ipratropium plus theophylline Other (n ) 16 September 2008 Annals of Internal Medicine Volume 149 Number 6 385

7 Article COPD Medications and Mortality Table 3. Adjusted Odds of Mortality Regimen Adjusted Odds Ratio (95% CI) All-Cause Mortality* Respiratory Death Cardiovascular Death Respiratory or Cardiovascular Death Medication None or short-acting -agonists only 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) Inhaled corticosteroids 0.80 ( ) 0.88 ( ) 0.80 ( ) 0.86 ( ) Ipratropium 1.11 ( ) 1.07 ( ) 1.34 ( ) 1.27 ( ) Long-acting -agonists 0.92 ( ) 1.12 ( ) 0.97 ( ) 0.98 ( ) Theophylline 1.05 ( ) 1.71 ( ) 1.16 ( ) 1.40 ( ) Medication regimen None or short-acting -agonists only 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) Inhaled corticosteroids 0.85 ( ) 0.97 ( ) 0.90 ( ) 0.93 ( ) Ipratropium 1.12 ( ) 1.06 ( ) 1.42 ( ) 1.42 ( ) Long-acting -agonists 0.93 ( ) 1.14 ( ) 1.08 ( ) 1.08 ( ) Theophylline 1.04 ( ) 1.71 ( ) 1.33 ( ) 1.33 ( ) Inhaled corticosteroids plus 0.88 ( ) 1.01 ( ) 1.04 ( ) 1.03 ( ) ipratropium Inhaled corticosteroids plus 0.82 ( ) 1.38 ( ) 1.16 ( ) 1.12 ( ) long-acting -agonists plus ipratropium Long-acting -agonists plus 1.03 ( ) 1.04 ( ) 1.14 ( ) 1.11 ( ) ipratropium Inhaled corticosteroids plus 0.78 ( ) 1.04 ( ) 0.79 ( ) 0.78 ( ) long-acting -agonists Ipratropium plus theophylline 1.17 ( ) 1.84 ( ) 1.47 ( ) 1.50 ( ) Inhaled corticosteroids plus 1.00 ( ) 2.00 ( ) 1.11 ( ) 1.10 ( ) ipratropium plus theophylline Other 0.86 ( ) 1.48 ( ) 1.33 ( ) 1.30 ( ) * Adjusted model includes systemic steroid use, inpatient exacerbations, outpatient exacerbations, number of short-acting -agonist fills, chronic heart failure, ischemic heart disease, cancer, digoxin, -blockers, -blockers, diuretics, lipid-lowering medications, angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs), insulin, oral hypoglycemics, and nonsteroidal anti-inflammatory drugs. Adjusted model includes systemic steroid use, inpatient exacerbations, outpatient exacerbations, chronic heart failure, and number of short-acting -agonist fills. Adjusted model includes systemic steroid use; inpatient exacerbations; outpatient exacerbations; chronic heart failure; ischemic heart disease; diabetes; number of short-acting -agonist fills; and exposure to digoxin, -blockers, -blockers, diuretics, calcium-channel blockers, lipid-lowering medications, ACE inhibitors, ARBs, insulin, oral hypoglycemics, and nonsteroidal anti-inflammatory drugs. Adjusted model includes systemic steroid use, inpatient exacerbations, outpatient exacerbations, chronic heart failure, ischemic heart disease, digoxin, -blockers, -blockers, diuretics, calcium-channel blockers, lipid-lowering medications, ACE inhibitors, ARBs, insulin, oral hypoglycemics, and nonsteroidal anti-inflammatory drugs. 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 -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 September 2008 Annals of Internal Medicine Volume 149 Number 6

8 COPD Medications and Mortality Article 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 -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 Figure 2. Risk for mortality associated with respiratory medications in the sensitivity analyses for each study end point. Sensitivity Analysis Subgroup Respiratory Death Cardiovascular Death All-Cause Mortality Actively treated patients 65 y Exposure by low and high dose Excluded combination /SABA Matched on CHF Decreased Risk for Death Adjusted Odds Ratio Increased Risk for Death Decreased Risk for Death Adjusted Odds Ratio Increased Risk for Death Decreased Risk for Death Adjusted Odds Ratio Increased Risk for Death Bars indicate 95% CIs. CHF chronic heart failure; inhaled corticosteroid; ipratropium; long-acting -agonist; SABA short-acting -agonist; theophylline September 2008 Annals of Internal Medicine Volume 149 Number 6 387

9 Article COPD Medications and Mortality 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 -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 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 -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 shortacting -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 allcause 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 war September 2008 Annals of Internal Medicine Volume 149 Number 6

10 COPD Medications and Mortality Article rants 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. From the Hines Veterans Affairs Hospital, Hines, Illinois; Northwestern University Feinberg School of Medicine, Chicago, Illinois; University of Illinois at Chicago, Chicago, Illinois; Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, Washington; and the American Board of Medical Specialties, Evanston, Illinois. 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 ). Potential Financial Conflicts of Interest: Honoraria: T.A. Lee (Astra- Zeneca, 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 Requests for Single Reprints: Todd A. Lee, PharmD, PhD, Hines Veterans Affairs Hospital, 5000 South 5th Avenue (151-H), Hines, IL 60141; , Current author addresses and author contributions are available at References 1. 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