Informing Healthcare Decisions with Observational Research Assessing Causal Effect. An Official American Thoracic Society Research Statement.

Rationale: Decisions in medicine are made on the basis of knowledge and reasoning, often in shared conversations with patients and families in consideration of clinical practice guideline recommendations, individual preferences, and individual goals. Observational studies can provide valuable knowledge to inform guidelines, decisions, and policy.Objectives: The American Thoracic Society (ATS) created a multidisciplinary ad hoc committee to develop a research statement to clarify the role of observational studies-alongside randomized controlled trials (RCTs)-in informing clinical decisions in pulmonary, critical care, and sleep medicine.Methods: The committee examined the strengths of observational studies assessing causal effects, how they complement RCTs, factors that impact observational study quality, perceptions of observational research, and, finally, the practicalities of incorporating observational research into ATS clinical practice guidelines.Measurements and Main Results: There are strengths and weakness of observational studies as well as RCTs. Observational studies can provide evidence in representative and diverse patient populations. Quality observational studies should be sought in the development of ATS clinical practice guidelines, and medical decision-making in general, when 1) no RCTs are identified or RCTs are appraised as being of low- or very low-quality (replacement); 2) RCTs are of moderate quality because of indirectness, imprecision, or inconsistency, and observational studies mitigate the reason that RCT evidence was downgraded (complementary); or 3) RCTs do not provide evidence for outcomes that a guideline committee considers essential for decision-making (e.g., rare or long-term outcomes; "sequential").Conclusions: Observational studies should be considered in developing clinical practice guidelines and in making clinical decisions.

AKI Treated with Renal Replacement Therapy in Critically Ill Patients with COVID-19.

BACKGROUND: AKI is a common sequela of coronavirus disease 2019 (COVID-19). However, few studies have focused on AKI treated with RRT (AKI-RRT). METHODS: We conducted a multicenter cohort study of 3099 critically ill adults with COVID-19 admitted to intensive care units (ICUs) at 67 hospitals across the United States. We used multivariable logistic regression to identify patient-and hospital-level risk factors for AKI-RRT and to examine risk factors for 28-day mortality among such patients. RESULTS: A total of 637 of 3099 patients (20.6%) developed AKI-RRT within 14 days of ICU admission, 350 of whom (54.9%) died within 28 days of ICU admission. Patient-level risk factors for AKI-RRT included CKD, men, non-White race, hypertension, diabetes mellitus, higher body mass index, higher d-dimer, and greater severity of hypoxemia on ICU admission. Predictors of 28-day mortality in patients with AKI-RRT were older age, severe oliguria, and admission to a hospital with fewer ICU beds or one with greater regional density of COVID-19. At the end of a median follow-up of 17 days (range, 1-123 days), 403 of the 637 patients (63.3%) with AKI-RRT had died, 216 (33.9%) were discharged, and 18 (2.8%) remained hospitalized. Of the 216 patients discharged, 73 (33.8%) remained RRT dependent at discharge, and 39 (18.1%) remained RRT dependent 60 days after ICU admission. CONCLUSIONS: AKI-RRT is common among critically ill patients with COVID-19 and is associated with a hospital mortality rate of >60%. Among those who survive to discharge, one in three still depends on RRT at discharge, and one in six remains RRT dependent 60 days after ICU admission.

Risk of Cardiovascular and Cerebrovascular Events in COPD Patients Treated With Long-Acting ß2-Agonist Combined With a Long-Acting Muscarinic or Inhaled Corticosteroid.

BACKGROUND: The recent approval of several fixed-dose combination long-acting ß2-agonist (LABA) and long-acting muscarinic antagonist (LAMA) products has increased the use of dual bronchodilators in the treatment of chronic obstructive pulmonary disease (COPD). Understanding the comparative safety of this combination is important for informing treatment decisions. OBJECTIVE: To compare the risk of cardiovascular and cerebrovascular (CCV) events associated with LABA/LAMA compared with a combination of LABA and inhaled corticosteroid (ICS). METHODS: This was a retrospective, observational cohort study using health insurance claims data to identify COPD patients initiating LABA/LAMA or LABA/ICS. CCV outcomes included hospitalizations with a primary diagnosis for acute coronary syndrome, heart failure, cardiac dysrhythmia, stroke, or transient ischemic attack. Patients were followed until they experienced an event, discontinued treatment, initiated medication from the opposite cohort, or lost enrollment. Patients were matched 1:4 on propensity scores, and time to event was compared using Cox proportional hazards models. RESULTS: After matching, there were 3842 patients in the LABA/LAMA cohort and 15 225 in the LABA/ICS cohort. Cardiovascular events in the LABA/LAMA cohort were lower than in the LABA/ICS: hazard ratio (HR) = 0.794; 95% CI = 0.623-0.997. No significant difference in the risk of cerebrovascular events (HR = 1.166; 95% CI = 0.653-1.959) was observed. CONCLUSIONS: Despite concerns about the CCV effects of LAMA and LABA monotherapy, the LABA/LAMA combination had similar or lower risk of these events in comparison to LABA/ICS. Further studies are recommended to confirm these findings.

Measuring health-related quality of life in chronic obstructive pulmonary disease: properties of the EQ-5D-5L and PROMIS-43 short form.

BACKGROUND: The Patient Reported Outcomes Measurement Information System 43-item short form (PROMIS-43) and the five-level EQ-5D (EQ-5D-5L) are recently developed measures of health-related quality of life (HRQL) that have potentially broad application in evaluating treatments and capturing burden of respiratory-related diseases. The aims of this study were: (1) to examine their psychometric properties in patients with chronic obstructive pulmonary disease (COPD), and (2) to identify dimensions of HRQL that differ and do not differ by lung function. METHODS: We conducted a multi-center, cross-sectional study ("COPD Outcomes-based Network for Clinical Effectiveness & Research Translation" [CONCERT]). We analyzed patients who met spirometric criteria for COPD, and completed EQ-5D-5L and PROMIS questionnaires. Disease severity was graded based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification. Pulmonary function test, PROMIS-43, EQ-5D (index score and EQ-Visual Analog Scale [EQ-VAS]), six minute walk test (6MWT), and three dyspnea scales (mMRC, Borg, FACIT-Dyspnea) were administered. Validity and reliability of EQ-5D-5L and PROMIS-43 were examined, and differences in HRQL by GOLD grade were assessed. RESULTS: Data from 670 patients with COPD were analyzed (mean age 68.5 years; 58% male). More severe COPD was associated with more problems with mobility, self-care and usual activities (all p-values <0.01) according to EQ-5D-5L. Related domains on EQ-5D-5L, PROMIS and clinical measures were moderately (r = 0.30-0.49) to strongly (r ≥ 0.50) correlated. A statistically significant trend of decreasing HRQL with more severe lung functions was observed for EQ-5D-5L index scores, EQ-VAS scores, and PROMIS physical function and social roles. CONCLUSIONS: Results supported the validity of EQ-5D-5L and PROMIS-43 in COPD patients, and indicate that physical function and social activities decrease with level of lung function by GOLD grade, but not pain, mental health, sleep or fatigue as reported by patients.

Use of spirometry in the diagnosis of COPD: a qualitative study in primary care.

Guidelines that recommend spirometry to confirm airflow obstruction among patients with suspected COPD are not routinely followed. We conducted a qualitative study to identify attitudes and barriers of primary care physicians to performing spirometry for patients with possible COPD. We conducted four focus groups, each with three primary care physicians (PCPs) who practice in an urban, academic medical center. In general, PCPs believed that spirometry was not necessary to confirm the diagnosis of COPD. Compared to other co-morbid conditions, in a patient with a diagnosis of COPD without self-reported symptoms, COPD was not a priority during a clinic visit. This was in part due to the belief that there was lack of evidence that medication used in COPD lead to improved outcomes and that there was no point of care measure for COPD compared to other co-morbid conditions such as diabetes mellitus or hypertension. Health system barriers specific to spirometry use was not identified. In conclusion, in our sample of PCPs, there was skepticism that spirometry is warranted to diagnose and manage COPD. Availability of spirometry was not a perceived barrier. Our results explain, in part, why previous interventions to improve access to spirometry and diagnosis of COPD in primary care settings have been difficult to conduct and/or have had marginal success. Our findings strongly suggest that a first step toward increasing the use of spirometry among primary care physicians is to have them believe in its utility in the diagnosis of COPD.

Risk of suicide attempt in asthmatic children and young adults prescribed leukotriene-modifying agents: a nested case-control study.

BACKGROUND: The US Food and Drug Administration has issued safety alerts about leukotriene receptor-modifying agents and suicidality/suicide, but because these were based on case reports, there is controversy about the association. OBJECTIVE: We conducted a nested case-control study to determine the association between leukotriene-modifying agents (LTMAs) and attempted suicide among asthmatic children and young adults. METHODS: Cases and control subjects were from a cohort of asthmatic patients aged 5 to 24 years who were new users of LTMAs or other asthma medications. Data were from an insurance claims database. Cases were defined as those with a suicide attempt (SA) occurring after exposure to asthma medication. Control subjects were persons at risk and were selected by using incidence density sampling in a 10:1 match. Conditional logistic regression was used to determine the association between LTMA exposure and the risk of attempted suicide adjusted for important covariates. RESULTS: We identified 344 cases and 3438 matched control subjects. Cases were more likely than control subjects to have risk factors for suicide. We found that current use of any LTMA was not associated with increased risk of an SA; in fact, the direction of effect was the opposite (adjusted odd ratio, 0.70; 95% CI, 0.36-1.39). CONCLUSION: In this analysis we found that use of LTMAs was not associated with an increased risk of SAs in children, adolescents, and young adults with asthma. Further research needs to be conducted to more fully understand the association between LTMAs and suicide, particularly in subpopulations.

Confirmatory spirometry for adults hospitalized with a diagnosis of asthma or chronic obstructive pulmonary disease exacerbation.

BACKGROUND: Objective measurement of airflow obstruction by spirometry is an essential part of the diagnosis of asthma or COPD. During exacerbations, the feasibility and utility of spirometry to confirm the diagnosis of asthma or chronic obstructive pulmonary disease (COPD) are unclear. Addressing these gaps in knowledge may help define the need for confirmatory testing in clinical care and quality improvement efforts. This study was designed to determine the feasibility of spirometry and to determine its utility to confirm the diagnosis in patients hospitalized with a physician diagnosis of asthma or COPD exacerbation. METHODS: Multi-center study of four academic healthcare institutions. Spirometry was performed in 113 adults admitted to general medicine wards with a physician diagnosis of asthma or COPD exacerbation. Two board-certified pulmonologists evaluated the spirometry tracings to determine the proportion of patients able to produce adequate quality spirometry data. Findings were interpreted to evaluate the utility of spirometry to confirm the presence of obstructive lung disease, according to the 2005 European Respiratory Society/American Thoracic Society recommendations. RESULTS: There was an almost perfect agreement for acceptability (κ = 0.92) and reproducibility (κ =0.93) of spirometry tracings. Three-quarters (73%) of the tests were interpreted by both pulmonologists as being of adequate quality. Of these adequate quality tests, 22% did not present objective evidence of obstructive lung disease. Obese patients (BMI ≥30 kg/m2) were more likely to produce spirometry tracings with no evidence of obstructive lung disease, compared to non-obese patients (33% vs. 8%, p = 0.007). CONCLUSIONS: Adequate quality spirometry can be obtained in most hospitalized adults with a physician diagnosis of asthma or COPD exacerbation. Confirmatory spirometry could be a useful tool to help reduce overdiagnosis of obstructive lung disease, especially among obese patients.

Design of the Reducing Diagnostic Error to Improve Patient Safety (REDEfINE) in COPD and asthma study: A cluster randomized comparative effectiveness trial.

Although spirometry is a simple, portable test and recommended for the diagnosis of asthma and chronic obstructive pulmonary disease (COPD), it is not routinely used in the primary care setting. Minorities and underserved populations are less likely to have spirometry assessment, leading to both over and misdiagnosis of asthma and COPD. Because dyspnea is a common symptom across multiple diseases, use of spirometry as a diagnostic tool is important. Missed, delayed, or misdiagnosis of asthma and COPD, which are considered diagnostic errors (DE), can lead to poor quality of care, increased morbidity and mortality, and increased costs to patients and health systems. Barriers to the use of spirometry have been identified at clinician/clinic and health systems levels. The REDEFINE program is designed to overcome identified barriers to spirometry use in primary care by utilizing health promoters (HPs) who perform spirometry within primary care clinics and work collaboratively with clinicians to incorporate the results at the point of care without interrupting clinic workflow. The REDEFINE trial is a comparative effectiveness study comparing outcomes of the REDEFINE program with usual care (UC) in primary care patients determined to be at increased risk of DE for asthma and COPD. The primary outcome will be all-cause hospitalizations. The secondary outcomes will be the proportion of accurate diagnosis of COPD, asthma, or asthma-COPD overlap based on initial diagnosis and spirometry and all cause and respiratory-related acute outpatient care and emergency department visits. In this report, we describe the design and methods for the REDEFINE trial. Trial registration: NCT03137303https://clinicaltrials.gov/ct2/show/NCT03137303?term=REDEFINE&draw=2&rank=1.

Determinants of spirometry use and accuracy of COPD diagnosis in primary care.

BACKGROUND: It is unclear if primary care physicians are following guidelines or using other patient characteristics and factors to determine when to perform spirometry in patients at risk for COPD. It is also unclear to what degree a diagnosis of COPD is accurately reflected by spirometry results. OBJECTIVES: To examine characteristics associated with use of spirometry in primary care for patients with increased risk for COPD and to determine the accuracy of COPD diagnosis in patients with spirometry. DESIGN: Retrospective cohort study. SUBJECTS: A cohort that met the following criteria was identified: ≥35 years of age; ≥ 2 primary care visits in internal medicine clinic in 2007; at least one respiratory or smoking cessation medication, or diagnosis of COPD or shortness of breath or dyspnea in 2007. MAIN MEASURES: Medical records of all primary care physician visits prior to the time of inclusion in 2007 were reviewed. Data on patient demographics, co-morbidities, respiratory medication use, presence of symptoms, history of tobacco use, and pulmonary function tests were extracted. KEY RESULTS: A total 1052 patients were identified. Dyspnea on exertion (Adjusted odds ratio (AOR) 1.52 [95% CI 1.06-2.18]) and chronic cough (AOR 1.71 [1.07-2.72]) were the only chronic symptoms associated with use of spirometry. Current (AOR 1.54 [0.99-2.40]) or past smoking (AOR 1.09 [0.72-1.65]) status were not associated with use of spirometry. Of the 159 patients with a diagnosis of COPD, 93 (58.5%) met GOLD criteria and 81(50.9%) met lower limit of normal (LLN) criteria for COPD. CONCLUSION: Clinicians use spirometry more often among patients with symptoms suggestive of COPD but not more often among patients with current or past tobacco use. For patients who had a spirometry and a diagnosis of COPD, primary care physicians were accurate in their diagnosis only half of the time.

The validity of using ICD-9 codes and pharmacy records to identify patients with chronic obstructive pulmonary disease.

BACKGROUND: Administrative data is often used to identify patients with chronic obstructive pulmonary disease (COPD), yet the validity of this approach is unclear. We sought to develop a predictive model utilizing administrative data to accurately identify patients with COPD. METHODS: Sequential logistic regression models were constructed using 9573 patients with postbronchodilator spirometry at two Veterans Affairs medical centers (2003-2007). COPD was defined as: 1) FEV1/FVC <0.70, and 2) FEV1/FVC < lower limits of normal. Model inputs included age, outpatient or inpatient COPD-related ICD-9 codes, and the number of metered does inhalers (MDI) prescribed over the one year prior to and one year post spirometry. Model performance was assessed using standard criteria. RESULTS: 4564 of 9573 patients (47.7%) had an FEV1/FVC < 0.70. The presence of ≥1 outpatient COPD visit had a sensitivity of 76% and specificity of 67%; the AUC was 0.75 (95% CI 0.74-0.76). Adding the use of albuterol MDI increased the AUC of this model to 0.76 (95% CI 0.75-0.77) while the addition of ipratropium bromide MDI increased the AUC to 0.77 (95% CI 0.76-0.78). The best performing model included: ≥6 albuterol MDI, ≥3 ipratropium MDI, ≥1 outpatient ICD-9 code, ≥1 inpatient ICD-9 code, and age, achieving an AUC of 0.79 (95% CI 0.78-0.80). CONCLUSION: Commonly used definitions of COPD in observational studies misclassify the majority of patients as having COPD. Using multiple diagnostic codes in combination with pharmacy data improves the ability to accurately identify patients with COPD.

COPD and asthma: Diagnostic accuracy requires spirometry.

Up to one-third of patients receiving a clinical diagnosis of COPD or asthma have been shown to lack evidence of disease in subsequent lung-function studies.

Geographic variation of spirometry use in newly diagnosed COPD.

BACKGROUND: Studies indicate that not all physicians in clinical practice use spirometry routinely in the diagnosis of COPD. Understanding the patterns of spirometry use across geographic regions in patients with newly diagnosed COPD may help to identify the factors associated with the use of spirometry and to improve the quality of COPD care. The objective of this study was to characterize the regional variation in spirometry use for patients with newly diagnosed COPD using the Healthcare Effectiveness Data and Information Set (HEDIS) 2006 spirometry performance measure. METHODS: We identified patients within the Veteran Health Administration who were >42 years of age who had received a new diagnosis of COPD between July 2003 and June 2004. The date of the COPD diagnosis was the index date. Spirometry use from 760 days prior to the index date to 180 days after the index date was identified. The Veterans Integrated Service Networks (VISNs) was used as the geographic unit for comparison. RESULTS: Of the 93,724 patients included in the study, 36.7% underwent spirometry during the study period. Using the largest VISN as the referent, there was more than a threefold difference in the adjusted odds ratios (AORs) for spirometry use between the regions with the lowest use (AOR, 0.52; 95% confidence interval [CI], 0.48 to 0.57) and the highest use (AOR, 1.61; 95% CI, 1.46 to 1.78). CONCLUSIONS: Overall, the use of spirometry in patients with newly diagnosed COPD was low using the new HEDIS spirometry measure with a significant regional variation comprising a more than threefold difference between the regions with the lowest and highest rates of spirometry use.

Medication use patterns associated with spirometry in diagnosing COPD.

Spirometry is necessary to diagnose and assess severity of COPD, but is used infrequently. Therapy with inhaled medications can improve COPD outcomes, but are not without risks. The use of spirometry may help mitigate the therapy risks if treatment is appropriate based on spirometry results. Before determining benefits of spirometry use, it is important to examine use of medications and the use of spirometry. Our objective was to characterize the association between the use of spirometry and respiratory medications in newly diagnosed COPD. This is a retrospective, longitudinal study using data from the Department of Veterans Affairs. We identified patients with a new diagnosis of COPD (index date). Spirometry use was measured two years before to six months after the index date. Respiratory medications were measured within one year following the index date. The association between spirometry and medication use was evaluated using logistic regressions and stratified by quintiles of the propensity scores for the probability of having had spirometry performed. A total of 81,162 patients were included and 30.8% had a spirometry performed. Patients with spirometry were more likely to have been dispensed an inhaled corticosteroid (AOR = 1.22 (95% CI, 1.11-1.36) to 1.61 (1.45-1.79)), long-acting beta-agonists (AOR = 1.41(1.25-1.58) to 1.63(1.45-1.83)), and ipratropium bromide (AOR = 1.25(1.16-1.35) to 1.64 (1.49-1.81)) across quintiles. Patients with spirometry were more likely to have medications added. The use of spirometry around a new diagnosis of COPD was associated with higher likelihood of using and adding respiratory medications after diagnosis.

Predicting Acute Exacerbations in Chronic Obstructive Pulmonary Disease.

BACKGROUND: With increasing health care costs that have outpaced those of other industries, payers of health care are moving from a fee-for-service payment model to one in which reimbursement is tied to outcomes. Chronic obstructive pulmonary disease (COPD) is a disease where this payment model has been implemented by some payers, and COPD exacerbations are a quality metric that is used. Under an outcomes-based payment model, it is important for health systems to be able to identify patients at risk for poor outcomes so that they can target interventions to improve outcomes. OBJECTIVE: To develop and evaluate predictive models that could be used to identify patients at high risk for COPD exacerbations. METHODS: This study was retrospective and observational and included COPD patients treated with a bronchodilator-based combination therapy. We used health insurance claims data to obtain demographics, enrollment information, comorbidities, medication use, and health care resource utilization for each patient over a 6-month baseline period. Exacerbations were examined over a 6-month outcome period and included inpatient (primary discharge diagnosis for COPD), outpatient, and emergency department (outpatient/emergency department visits with a COPD diagnosis plus an acute prescription for an antibiotic or corticosteroid within 5 days) exacerbations. The cohort was split into training (75%) and validation (25%) sets. Within the training cohort, stepwise logistic regression models were created to evaluate risk of exacerbations based on factors measured during the baseline period. Models were evaluated using sensitivity, specificity, and positive and negative predictive values. The base model included all confounding or effect modifier covariates. Several other models were explored using different sets of observations and variables to determine the best predictive model. RESULTS: There were 478,772 patients included in the analytic sample, of which 40.5% had exacerbations during the outcome period. Patients with exacerbations had slightly more comorbidities, medication use, and health care resource utilization compared with patients without exacerbations. In the base model, sensitivity was 41.6% and specificity was 85.5%. Positive and negative predictive values were 66.2% and 68.2%, respectively. Other models that were evaluated resulted in similar test characteristics as the base model. CONCLUSIONS: In this study, we were not able to predict COPD exacerbations with a high level of accuracy using health insurance claims data from COPD patients treated with bronchodilator-based combination therapy. Future studies should be done to explore predictive models for exacerbations. DISCLOSURES: No outside funding supported this study. Samp is now employed by, and owns stock in, AbbVie. The other authors have nothing to disclose. Study concept and design were contributed by Joo and Pickard, along with the other authors. Samp and Lee performed the data analysis, with assistance from the other authors. Samp wrote the manuscript, which was revised by Schumock and Calip, along with the other authors.

Geographic variation in chronic obstructive pulmonary disease exacerbation rates.

BACKGROUND: Exacerbations are important disease events for patients with chronic obstructive pulmonary disease (COPD) as they are relatively frequent, result in significant resource use and can indicate worsening disease. Little is known about variation in COPD exacerbation rates across a health system in various geographic regions. OBJECTIVE: To compare COPD exacerbation rates by regional service networks called Veterans Integrated Service Network (VISN) in the Veterans Health Administration (VA) system. DESIGN: Retrospective, observational study. SUBJECTS: Patients with a COPD diagnosis from October 1999 to September 2000 with follow-up to September 2002. MEASUREMENTS: Acute exacerbations of COPD during the baseline and follow-up periods. RESULTS: A total of 198,981 patients were identified. Average exacerbation rate at baseline was 0.503 events per person per year. In the follow-up period, there were 187,686 exacerbations experienced by 87,494 persons (44.0% of cohort). During follow-up, the average adjusted exacerbation rate was 0.589 per person per year and varied from 0.335 (95% CI, 0.328-0.342) in VISN 1 to 0.749 (95% CI, 0.735-0.0.763) in VISN 9. Using the median rate of exacerbation during the baseline period as the referent, 9 VISNs had lower adjusted rate ratios and 12 VISNs had higher adjusted rate ratios in the follow-up period. CONCLUSIONS: Geographic variation in the VA VISN system supports evidence that the medical care system including provider factors, and less so patient factors, affect COPD exacerbations. Understanding the reasons underlying this variation in COPD exacerbation rates may lead to improvements in future care and outcomes.

Comparative Effectiveness of Long-Acting Beta2 -Agonist Combined with a Long-Acting Muscarinic Antagonist or Inhaled Corticosteroid in Chronic Obstructive Pulmonary Disease.

INTRODUCTION: Several dual bronchodilator fixed-dose inhaler medications were recently approved for the treatment of chronic obstructive pulmonary disease (COPD). These products combine a long-acting ß2 -agonist (LABA) and long-acting muscarinic antagonist (LAMA). In clinical trials, the separate mechanisms of the bronchodilators resulted in improved lung function. COPD treatment guidelines currently recommend combination LABA/LAMA as alternative therapy to combination LABA/inhaled corticosteroid (ICS). Evidence is limited on the comparative effectiveness of LABA/LAMA and LABA/ICS in COPD. The objective of this study was to compare real-world COPD exacerbation rates among patients treated with LABA/LAMA with those treated with LABA/ICS. METHODS: This was a retrospective observational study of COPD patients in the United States treated with LABA/LAMA or LABA/ICS combination. Insurance claims from January 1, 2004, through December 31, 2014, were used as the data source. Patients were required to have greater than one prescription filled for the combination medications, and they were followed from 30 days after drug initiation. Individuals were censored if they discontinued a study medication, initiated medication from the opposite cohort (LAMA or ICS), lost enrollment eligibility, or at the study period end. Exacerbation rates were compared using Poisson regression. RESULTS: There were 5384 patients in the LABA/LAMA cohort and 473,388 patients in the LABA/ICS cohort. The LABA/LAMA cohort was older, had more comorbidities, and more severe COPD. Unadjusted annual exacerbation rates were 2.87 events per person-year (standard deviation [SD] 5.14) in the LABA/LAMA cohort and 1.68 (SD 9.82) in the LABA/ICS cohort. The adjusted incidence rate ratio was 0.98 (95% confidence interval 0.95-1.01) for LABA/LAMA compared with LABA/ICS. CONCLUSIONS: The LABA/LAMA combination had similar effectiveness to LABA/ICS as measured by exacerbation rates in COPD patients. As a result, characteristics other than effectiveness, such as symptom control, cost, patient preferences, and adverse events, may be important in selecting between the two regimens.

An Official American Thoracic Society Workshop Report. A Framework for Addressing Multimorbidity in Clinical Practice Guidelines for Pulmonary Disease, Critical Illness, and Sleep Disorders.

Coexistence of multiple chronic conditions (i.e., multimorbidity) is the most common chronic health problem in adults. However, clinical practice guidelines have primarily focused on patients with a single disease, resulting in uncertainty about the care of patients with multimorbidity. The American Thoracic Society convened a workshop with the goal of establishing a strategy to address multimorbidity within clinical practice guidelines. In this Workshop Report, we describe a framework that addresses multimorbidity in each of the key steps of guideline development: topic selection, panel composition, identifying clinical questions, searching for and synthesizing evidence, rating the quality of that evidence, summarizing benefits and harms, formulating recommendations, and rating the strength of the recommendations. For the consideration of multimorbidity in guidelines to be successful and sustainable, the process must be both feasible and pragmatic. It is likely that this will be achieved best by the step-wise addition and refinement of the various components of the framework.

Interventions to reduce rehospitalizations after chronic obstructive pulmonary disease exacerbations. A systematic review.

RATIONALE: Approximately 20% of patients hospitalized for COPD exacerbations in the United States will be readmitted within 30 days. The Centers for Medicare and Medicaid Services has recently proposed to revise the Hospital Readmissions Reduction Program to financially penalize hospitals with high all-cause 30-day rehospitalization rates after a hospitalization for COPD exacerbation on or after October 1, 2014. OBJECTIVES: To report the results of a systematic review of randomized clinical trials evaluating interventions to reduce the rehospitalizations after COPD exacerbations. METHODS: Multiple electronic databases were systematically searched to identify relevant studies published between January 1966 and June 2013. Titles, abstracts, and, subsequently, full-text articles were assessed for eligibility. Each study was appraised using predefined criteria. MEASUREMENTS AND MAIN RESULTS: Among 913 titles and abstracts screened, 5 studies (1,393 participants) met eligibility criteria. All studies had a primary outcome of rehospitalization at 6 or 12 months. No study examined 30-day rehospitalization as the primary outcome. Each study tested a different set of interventions. Two studies (one conducted in Canada and one conducted in Spain and Belgium) showed a decrease in all-cause rehospitalization over 12 months in the intervention group versus comparator group (mean number of hospitalizations per patient, 1.0 vs. 1.8; P = 0.01; percent hospitalized, 45 vs. 67%; P = 0.028; respectively). The only study conducted in the United States found a greater than twofold higher risk of mortality in the intervention group (17 vs. 7%, P = 0.003) but no significant difference in rehospitalizations. It was unclear which set of interventions was effective or harmful. CONCLUSIONS: The evidence base is inadequate to recommend specific interventions to reduce rehospitalizations in this population and does not justify penalizing hospitals for high 30-day rehospitalization rates after COPD exacerbations.

Complexity of medication use in newly diagnosed chronic obstructive pulmonary disease patients.

BACKGROUND: To better understand how medications have been used and the complexity of regimens used to treat patients, we characterized patterns of medication use and the degree to which patients used different classes of medications in combination and over time in a cohort of newly diagnosed chronic obstructive pulmonary disease (COPD) patients. OBJECTIVE: The objectives of this study were to characterize patterns of medication use, including the degree to which patients used different classes of medications in combination and over time within a cohort of newly diagnosed COPD patients and to identify the proportion of patients who had gaps in filling their prescriptions. METHODS: We identified a cohort of patients from the Veterans Affairs health care system with newly diagnosed COPD between 1999 and 2003. Using prescription fill information, we quantified the prevalence and incidence of exposure to short-acting ß-agonists (SABAs), long-acting ß-agonists (LABAs), short-acting anticholinergics (eg, ipratropium [IPRA]), and inhaled corticosteroids (ICSs) over 1 year. We additionally characterized the sequencing of medication addition and discontinuation and gaps between prescription fills. The prevalence of multiple respiratory medication use was summarized at 90, 180, and 365 days of follow-up. RESULTS: Of 133,737 patients with newly diagnosed COPD, the majority (80.0%) used a SABA, followed by 40.0% using IPRA, 33.2% using an ICS and 16.0% using a LABA during the 1-year follow-up. Medication changes were frequent, with 57.7% of patients having a medication addition and 48.6% discontinuing medication. The sequence of medication changes varied greatly across patients. Multiple respiratory medication use was common, with 29% of patients dispensed 3 to 4 medication classes in 1 year. CONCLUSIONS: Many COPD patients who are started on medication management undergo changes in prescribed pharmacotherapy and are taking multiple medications. Despite clinical practice guidelines, there is an ad hoc nature of COPD medication management, and such heterogeneity challenges the ability to estimate relationships between drug exposure and outcomes using real-world data.