Brian Bartle

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 patients 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

Medication adherence and persistence in the last year of life in COPD patients.

OBJECTIVE To examine medication adherence and persistence among COPD patients during their last year of life. DATA SOURCE National VA databases were used to identify patients who had COPD and died between 1999 and 2003. STUDY DESIGN We examined use of inhaled corticosteroids (ICS), long acting beta(2) agonists (LABA), methylxanthines (MTX), and anticholinergics (AC), alone and in combination. Medication possession ratios (MPR) were compared between regimens by quarterly periods using General Estimating Equations (GEE). Medication persistence was examined in monotherapy users with Kaplan-Meier survival analysis and extended Cox proportional hazard models. PRINCIPAL FINDINGS Only half of the identified patients in the COPD cohort (5913 of 11,376) used any medications. Among 5913 patients, overall mean (SD) MPR was 0.44 (0.32) during the last year of life. A positive linear trend in MPR was observed across quarterly periods in AC users (beta=0.014, p<0.0001), and was highest for MTX users (beta=0.11, p<0.0001). Of 3436 on monotherapy only, 40% discontinued medication within 30 days, and 70% discontinued within 90 days. MTX users were less likely to discontinue (HR=0.714, p=0.012) than reference (AC) group. CONCLUSION COPD patients in their last year of life tended to use respiratory medications sporadically. Further research is needed to qualify whether minor differences in MPR between regimens reflect behavioral differences related to regimen or reflect refill policy and MPR calculation technique.

Coexisting chronic conditions associated with mortality and morbidity in adult patients with asthma

Abstract Objective: Many asthma patients suffer from chronic conditions other than asthma. We investigated the specific contribution of common comorbidities on mortality and morbidity in adult asthma. Methods: In an observational study of adults with incident asthma identified between 1999 and 2003 using National Veterans Affairs and Centers for Medicare and Medicaid Services encounter databases (n = 25 975, follow-up 3.0 ± 1.7 years), association between 13 most prevalent comorbidities (hypertension, ischemic heart disease (IHD), osteoarthritis, rheumatoid arthritis, diabetes, mental disorders, substance/drug abuse, enlarged prostate, depression, cancer, alcoholism, HIV and heart failure) and four conditions previously associated with asthma (sleep apnea, gastroesophageal reflux disease (GERD), rhinitis and sinusitis) and mortality, hospitalizations and asthma exacerbations were assessed using multivariate regression analyses adjusted for other clinically important covariates. Results: HIV followed by alcoholism and mental disorders among 18–45-years old, and heart failure, diabetes, IHD and cancer among those ≥65 years old were associated with an increased risk of all-cause mortality. Many conditions were associated with increased risk for all-cause hospitalizations, but the increased risk was consistent across all ages for mental disorders. For asthma exacerbations, mental disorder followed by substance abuse and IHD were associated with increased risk among those 18–45 years old, and chronic sinusitis, mental disorder and IHD among those ≥65-years old. GERD was associated with decreased risk for asthma exacerbation in all ages. Conclusions: Many comorbidities are associated with poor outcome in adult asthmatics and their effect differs by age. Mental disorders are associated with increased risk of mortality and morbidity across ages.

Mortality Risk in Patients Receiving Drug Regimens with Theophylline for Chronic Obstructive Pulmonary Disease

Study Objective. To evaluate outcomes associated with six treatment regimens with theophylline versus each regimen without theophylline in patients with chronic obstructive pulmonary disease (COPD).

Diabetic foot ulcer severity predicts mortality among veterans with type 2 diabetes

AIM Diabetic foot ulcers are associated with an increased risk of death. We evaluated whether ulcer severity at presentation predicts mortality. METHODS Patients from a national, retrospective, cohort of veterans with type 2 diabetes who developed incident diabetic foot ulcers between January 1, 2006 and September 1, 2010, were followed until death or the end of the study period, January 1, 2012. Ulcers were characterized as early stage, osteomyelitis, or gangrene at presentation. Cox proportional hazard regression identified independent predictors of death, controlling for comorbidities, laboratory parameters, and healthcare utilization. RESULTS 66,323 veterans were included in the cohort and followed for a mean of 27.7months: 1-, 2-, and 5-year survival rates were 80.80%, 69.01% and 28.64%, respectively. Compared to early stage ulcers, gangrene was associated with an increased risk of mortality (HR 1.70, 95% CI 1.57-1.83, p<0.001). The magnitude of this effect was greater than diagnosed vascular disease, i.e., coronary artery disease, peripheral arterial disease, or stroke. CONCLUSION Initial diabetic foot ulcer severity is a more significant predictor of subsequent mortality than coronary artery disease, peripheral arterial disease, or stroke. Unrecognized or under-estimated vascular disease and/or sepsis secondary to gangrene should be explored as possible causal explanations.

Association between chronic illness complexity and receipt of evidence-based depression care

Background:The rate of guideline concordance with antidepressant treatment for persons with depression is low. The problem may be even more pronounced for patients with depression and other multiple chronic conditions (MCC). Objectives:To study, for persons with new depressive episodes, the association between MCC and the likelihood of receiving guideline-concordant depression treatment. Research Design:Retrospective cohort study using Veterans Affairs administrative data. Subjects:A total of 43,189 Veterans Affairs patients who had a new depressive episode during 2007 were included. Measures:We assessed whether patients had an adequate supply of antidepressants during acute and continuation phases of depression treatment, which indicates guideline-concordant care. We determined the association between comorbid conditions and receipt of adequate antidepressant supplies after adjusting for potential confounders. Results:Compared with patients with depression alone, those with comorbid cardiovascular/cerebrovascular disease, peptic ulcer/gastroesophageal reflux disease (GERD), or arthritis were 8%–13% more likely to receive adequate antidepressant supplies during the acute phase. Patients with depression and substance/alcohol abuse were 15% less likely to receive adequate supplies in the acute treatment phase. Those with cardiovascular/cerebrovascular disease or peptic ulcer/GERD were 9%–10% more likely to receive continuation phase guideline-concordant depression treatment. Patients with comorbid substance/alcohol abuse were 19% less likely to receive continuation phase guideline-concordant depression treatment. Relatively few of the most prevalent MCC clusters were significantly associated with receipt of guideline-concordant depression treatment. Conclusions:There was no consistent association between specific clusters of chronic conditions and adequate antidepressant supplies. There continues to be need for practice-level and system-level interventions to increase quality of depression treatment, particularly among persons with certain comorbid conditions such as cardiovascular/cerebrovascular disease, peptic ulcer/GERD, and arthritis.

Coded Cause of Death and Timing of COPD Diagnosis

The aims of this study were to characterize causes of death among veterans with COPD using multiple cause of death coding, and to examine whether causes of death differed according to timing of COPD diagnosis. Veterans with COPD who died during a five-year follow-up period were identified from national VA databases linked to National Death Index files. Primary, secondary, underlying, and all-coded causes of death were compared between recent and preexistent COPD cohorts using proportional mortality ratios (PMRs), which compares proportion dying from specific causes as opposed to absolute risk of death. Of 26,357 decedents, 7,729 were categorized preexistent and 18,628 were recent COPD cases. Unspecified COPD was listed as underlying cause of death in a significantly greater proportion of preexistent COPD cases compared to recent cases, 20% vs 10%, PMR = 2.0 (95% CI: 1.9–2.1). A relatively higher proportion of recently diagnosed cases died from lung/bronchus, prostate, and site-unspecified cancers. Respiratory failure (J969) was rarely coded as an underlying or primary cause (< 1%), but was a second-code cause of death in 9% of recent and 12% of preexistent cases. Differences in coded causes of death between patients with a recent diagnosis of COPD compared to a preexistent diagnosis of COPD suggests that there is either coded cause-related bias or true differences in cause of death related to length of time with diagnosis. Thus, methods used to identify cohorts of COPD patients, i.e., incidence versus prevalence-based approaches, and coded cause of death can affect estimates of cause-specific mortality.