Risk for Death Associated with Medications for Recently Diagnosed Chronic Obstructive Pulmonary Disease

Context Many think we need more information about the safety of respiratory medications for chronic obstructive pulmonary disease (COPD). Contribution This large casecontrol 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 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 eventssuch as death associated with medication usemay 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 medicationsparticularly 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. Methods We conducted this nested casecontrol 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. Cohort 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. Case Patients 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. Control Participants 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 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 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 -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