Association of Guideline-Recommended COPD Inhaler Regimens With Mortality, Respiratory Exacerbations, and Quality of Life: A Secondary Analysis of the Long-Term Oxygen Treatment Trial.

BACKGROUND: Although inhaled therapy reduces exacerbations among patients with COPD, the effectiveness of providing inhaled treatment per risk stratification models remains unclear. RESEARCH QUESTION: Are inhaled regimens that align with the 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy associated with clinically important outcomes? STUDY DESIGN AND METHODS: We conducted secondary analyses of Long-term Oxygen Treatment Trial (LOTT) data. The trial enrolled patients with COPD with moderate resting or exertional hypoxemia between 2009 and 2015. Our exposure was the patient-reported inhaled regimen at enrollment, categorized as either aligning with, undertreating, or potentially overtreating per the 2017 GOLD strategy. Our primary composite outcome was time to death or first hospitalization for COPD. Additional outcomes included individual components of the composite outcome and time to first exacerbation. We generated multivariable Cox proportional hazard models across strata of GOLD-predicted exacerbation risk (high vs low) to estimate between-group hazard ratios for time to event outcomes. We adjusted models a priori for potential confounders, clustered by site. RESULTS: The trial enrolled 738 patients (73.4% men; mean age, 68.8 years). Of the patients, 571 (77.4%) were low risk for future exacerbations. Of the patients, 233 (31.6%) reported regimens aligning with GOLD recommendations; most regimens (54.1%) potentially overtreated. During a 2.3-year median follow-up, 332 patients (44.9%) experienced the composite outcome. We found no difference in time to composite outcome or death among patients reporting regimens aligning with recommendations compared with undertreated patients. Among patients at low risk, potential overtreatment was associated with higher exacerbation risk (hazard ratio, 1.42; 95% CI, 1.09-1.87), whereas inhaled corticosteroid treatment was associated with 64% higher risk of pneumonia (incidence rate ratio, 1.64; 95% CI, 1.01-2.66). INTERPRETATION: Among patients with COPD with moderate hypoxemia, we found no difference in clinical outcomes between inhaled regimens aligning with the 2017 GOLD strategy compared with those that were undertreated. These findings suggest the need to reevaluate the effectiveness of risk stratification model-based inhaled treatment strategies.

Characteristics at the time of oxygen initiation associated with its adherence: Findings from the COPD Long-term Oxygen Treatment Trial.

RATIONALE: Characteristics associated with adherence to long-term oxygen therapy (LTOT) in COPD remain unclear. OBJECTIVES: To identify patient characteristics at the time of oxygen initiation associated with its adherence. METHODS: We conducted a secondary analysis of data from 359 COPD participants assigned to oxygen in the Long-term Oxygen Treatment Trial. Participants were prescribed continuous (n = 214) or intermittent (n = 145) oxygen based on desaturation patterns at study entry. At the time of initial prescription, participants rated their perceived readiness, confidence, and importance to use oxygen on a 0-10 scale (0 = not at all, 10 = very much). During follow-up, they self-reported average hours per day of use (adherence). Adherence was averaged over short-term (0-30 days), medium-term (months 9-12), and long-term (month 13 to last follow-up) intervals. Multivariable logistic regression models explored characteristics associated with high adherence (≥16 h/day [continuous] or ≥8 h/day [intermittent]) during each time interval. RESULTS: Participant readiness, confidence, and importance at the time of oxygen initiation were associated with high short- and medium-term adherence. For each unit increase in baseline readiness, the odds of high short-term adherence increased by 21% (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.05-1.40) and 94% (OR 1.94, 95% CI 1.45-2.59) in the continuous and intermittent groups, respectively. In both groups, high adherence in the medium-term was associated with high adherence in the long-term (continuous, OR 12.49, 95% CI 4.90-31.79; intermittent, OR 38.08, 95% CI 6.96-208.20). CONCLUSIONS: Readiness, confidence, and importance to use LTOT at initiation, and early high adherence, are significantly associated with long-term oxygen adherence.

The Long-Term Oxygen Treatment Trial for Chronic Obstructive Pulmonary Disease: Rationale, Design, and Lessons Learned.

The Long-Term Oxygen Treatment Trial demonstrated that long-term supplemental oxygen did not reduce time to hospital admission or death for patients who have stable chronic obstructive pulmonary disease and resting and/or exercise-induced moderate oxyhemoglobin desaturation, nor did it provide benefit for any other outcome measured in the trial. Nine months after initiation of patient screening, after randomization of 34 patients to treatment, a trial design amendment broadened the eligible population, expanded the primary outcome, and reduced the goal sample size. Within a few years, the protocol underwent minor modifications, and a second trial design amendment lowered the required sample size because of lower than expected treatment group crossover rates. After 5.5 years of recruitment, the trial met its amended sample size goal, and 1 year later, it achieved its follow-up goal. The process of publishing the trial results brought renewed scrutiny of the study design and the amendments. This article expands on the previously published design and methods information, provides the rationale for the amendments, and gives insight into the investigators' decisions about trial conduct. The story of the Long-Term Oxygen Treatment Trial may assist investigators in future trials, especially those that seek to assess the efficacy and safety of long-term oxygen therapy. Clinical trial registered with clinicaltrials.gov (NCT00692198).

A Randomized Trial of Long-Term Oxygen for COPD with Moderate Desaturation.

BACKGROUND: Long-term treatment with supplemental oxygen has unknown efficacy in patients with stable chronic obstructive pulmonary disease (COPD) and resting or exercise-induced moderate desaturation. METHODS: We originally designed the trial to test whether long-term treatment with supplemental oxygen would result in a longer time to death than no use of supplemental oxygen among patients who had stable COPD with moderate resting desaturation (oxyhemoglobin saturation as measured by pulse oximetry [Spo2], 89 to 93%). After 7 months and the randomization of 34 patients, the trial was redesigned to also include patients who had stable COPD with moderate exercise-induced desaturation (during the 6-minute walk test, Spo2 ≥80% for ≥5 minutes and <90% for ≥10 seconds) and to incorporate the time to the first hospitalization for any cause into the new composite primary outcome. Patients were randomly assigned, in a 1:1 ratio, to receive long-term supplemental oxygen (supplemental-oxygen group) or no long-term supplemental oxygen (no-supplemental-oxygen group). In the supplemental-oxygen group, patients with resting desaturation were prescribed 24-hour oxygen, and those with desaturation only during exercise were prescribed oxygen during exercise and sleep. The trial-group assignment was not masked. RESULTS: A total of 738 patients at 42 centers were followed for 1 to 6 years. In a time-to-event analysis, we found no significant difference between the supplemental-oxygen group and the no-supplemental-oxygen group in the time to death or first hospitalization (hazard ratio, 0.94; 95% confidence interval [CI], 0.79 to 1.12; P=0.52), nor in the rates of all hospitalizations (rate ratio, 1.01; 95% CI, 0.91 to 1.13), COPD exacerbations (rate ratio, 1.08; 95% CI, 0.98 to 1.19), and COPD-related hospitalizations (rate ratio, 0.99; 95% CI, 0.83 to 1.17). We found no consistent between-group differences in measures of quality of life, lung function, and the distance walked in 6 minutes. CONCLUSIONS: In patients with stable COPD and resting or exercise-induced moderate desaturation, the prescription of long-term supplemental oxygen did not result in a longer time to death or first hospitalization than no long-term supplemental oxygen, nor did it provide sustained benefit with regard to any of the other measured outcomes. (Funded by the National Heart, Lung, and Blood Institute and the Centers for Medicare and Medicaid Services; LOTT ClinicalTrials.gov number, NCT00692198 .).

Assessing future need for acute care in adult asthmatics: the Profile of Asthma Risk Study: a prospective health maintenance organization-based study.

STUDY OBJECTIVES: To develop simple clinical tools predictive of acute asthma care and to identify modifiable risk factors. DESIGN: Prospective cohort study. SETTING: A large health maintenance organization (430,000 members). PATIENTS/PARTICIPANTS: Adult members (18 to 55 years old) with asthma. INTERVENTIONS: Data from a questionnaire, skin-prick testing for inhalant allergens, and spirometry were collected at the baseline visit. Acute care utilization data were obtained from administrative databases for a subsequent 30-month period. METHODS: This two-phase study first identified and performed a split-sample validation on three clinical tools to determine their predictive ability by employing data from a questionnaire, questionnaire plus spirometry, and questionnaire plus spirometry and skin-prick testing. Second, it identified modifiable independent risk factors. MEASUREMENTS AND RESULTS: The 554 study participants generated 173 episodes of acute care over 1,258 person-years of follow-up (0.14 episodes per person per year). Of these, 101 participants had at least one episode, and one third of this group had two or more episodes. Clinical scoring into risk groups was done by reverse stepwise regression analyses. Using relative risks (RRs) as a guide, high-risk, moderate-risk, and low-risk groups were identified. The high-risk groups, 13 to 21% of the validation sample, had a 7- to 11-fold increased risk for hospital care compared to the low-risk groups. The moderate-risk groups, 46 to 50% of the validation sample, had a twofold- to fourfold-increased risk. FEV(1) was the most significant predictor (RR, 4.33). Of the four potentially modifiable risk factors identified, current cigarette smoke exposure (RR, 1.6) and ownership and skin-prick test positivity to cat or dog (RR, 1.5) were the most significant. CONCLUSIONS: These models stratify asthma patients at risk for acute care. Patients with lower FEV(1) values are at significantly higher risk, underscoring the importance of spirometry in asthma care.

Use and impact of an automated telephone outreach system for asthma in a managed care setting.

OBJECTIVE: To test the ability of an automated telephone outreach intervention to reduce acute healthcare utilization and improve quality of life among adult asthma patients in a large managed care organization. STUDY DESIGN: Randomized clinical trial. METHODS: Patients with persistent asthma were randomly assigned to telephone outreach (automated = 3389, live caller = 192) or usual care (n = 3367). Intervention participants received 3 outreach calls over a 10-month period. The intervention provided brief, supportive information and flagged individuals with poor asthma control for follow-up by a provider. A survey was mailed to 792 intervention participants and 236 providers after the intervention. Additional feedback was obtained as part of the final intervention contact. RESULTS: The intent-to-treat analysis found no significant differences between the intervention and usual-care groups for medication use, healthcare utilization, asthma control, or quality of life. Post hoc analyses found that, compared with the control group, individuals who actually participated in the intervention were significantly more likely to use inhaled steroids and to have had a routine medical visit for asthma during the follow-up period and less likely to use short-acting beta-agonists. They also reported higher satisfaction with their asthma care and better asthma-specific quality of life. Of surveyed providers, 59% stated the program helped them to clinically manage their asthma patients and 70% thought the program should be continued. CONCLUSIONS: This study did not find improved health outcomes in the primary analyses. The intervention was well accepted by providers, however, and the individuals who participated in the calls appeared to have benefited from them. These findings suggest that further studies of automated telephone outreach interventions seem warranted.

Development and validation of a medication intensity scale derived from computerized pharmacy data that predicts emergency hospital utilization for persistent asthma.

OBJECTIVE: To validate a risk stratification scheme using computerized pharmacy data to predict emergency hospital utilization for persistent asthma. STUDY DESIGN: Retrospective cohort. METHODS: The development sample consisted of 1079 HMO members aged 18 to 56 years with persistent asthma. The scale used medication cut-points as predictors for next-year emergency hospital utilization in a stepwise logistic regression model. Prediction properties were evaluated in a validation sample of 24 370 patients aged 18 to 56 years in a separate persistent-asthma database. RESULTS: Increasing use of beta-agonists (odds ratio [OR] of 2.2 for 5-13 vs 0-4 canisters; OR of 2.4 for >13 vs 5-13 canisters) and oral corticosteroids (OR of 2.6 for >2 vs 0-2 dispensing events) in the first year independently predicted emergency hospital utilization in the second year. Assigning 1 point for exceeding each of the above 3 medication thresholds led to a 4-level medication intensity scale that was significantly (P <.0001) related to validated measures of asthma symptom severity, asthma control, and asthma quality of life in the development sample. In the validation sample, this scheme identified a high-risk group that was 6 times more likely than the low-risk group to require subsequent emergency hospital care, with overall sensitivity of 65% and specificity of 54%. This scale did not perform as well as a scale based on both baseline emergency hospital care and pharmacy data. CONCLUSION: This simple risk stratification scheme can be used for populations with persistent asthma for whom computerized pharmacy data, but not computerized prior utilization data, are available.

The controller-to-total asthma medication ratio is associated with patient-centered as well as utilization outcomes.

BACKGROUND: The ratio of controller medication to total asthma medications has been related to asthma utilization outcomes, but its relationship to patient-centered outcomes has not been explored. METHODS: Surveys that included validated asthma quality-of-life, control, and symptom severity tools were completed by a random sample of 2,250 health maintenance organization members aged 18 to 56 years who had persistent asthma. Linked computerized pharmacy data provided dispensing information on beta-agonist canisters and asthma controller medication. The ratio was calculated as the number of controller medications dispensed during the year of the survey divided by the total number medications (ie, inhaled beta-agonist plus controller medications) dispensed. The relationships of the optimal ratio cutoff to patient-centered outcomes and to subsequent acute asthma exacerbations were determined. RESULTS: Mean asthma quality-of-life, asthma control, and symptom severity scale scores were significantly (p < 0.0001) more favorable in patients with ratios of > or = 0.5. After adjusting for demographic characteristics, patients with ratios of > or = 0.5 were significantly less likely to have adverse results regarding asthma quality of life (odds ratio [OR], 0.65; 95% confidence interval [CI], 0.52 to 0.80), asthma control (OR, 0.62; 95% CI, 0.50 to 0.77), and symptom severity (OR, 0.53; 95% CI, 0.43 to 0.65), and were also less likely to experience subsequent asthma hospitalizations or emergency department visits (OR, 0.44; 95% CI, 0.26 to 0.74) than patients with lower ratios. CONCLUSION: A higher controller medication/total asthma medication ratio is associated with better patient-centered asthma outcomes as well as with reduced emergency hospital utilization. This adds further support to the use of the medication ratio as an asthma quality-of-care measure.

Validation of a beta-agonist long-term asthma control scale derived from computerized pharmacy data.

BACKGROUND: Asthma control has been defined clinically by using validated tools, but an asthma control scale using administrative data has not been reported. OBJECTIVE: We sought to validate a beta-agonist asthma control scale derived from administrative data. METHODS: Surveys that included validated asthma symptom and control tools were completed by a random sample of 2250 health maintenance organization members aged 18 to 56 years with persistent asthma. Linked computerized pharmacy data provided beta-agonist canister and oral corticosteroid dispensings. The proposed 4-level asthma control scale was based on the number of short-acting beta-agonist canisters dispensed in 12 months. Construct validity and predictive validity were assessed. RESULTS: For construct validity, factor analysis showed significant loading of the beta-agonist scale on the symptom control factor, and the beta-agonist scale was significantly related to the validated asthma control and symptom scales (r = 0.31, P < .0001). For predictive validity, each progressive level of the proposed beta-agonist control scale was associated with an increased risk of subsequent asthma hospitalizations or emergency department visits and oral corticosteroid use, independent of prior use. CONCLUSION: A scale based on the number of beta-agonists dispensed in a 1-year period and derived from administrative data reflects asthma symptom control over that period of time. This scale can help identify patients who are at risk for future acute asthma health care use. CLINICAL IMPLICATIONS: This information can be used in population management and by clinicians to assess long-term asthma control and identify patients who need intervention to prevent future morbidity.

Improved asthma outcomes from allergy specialist care: a population-based cross-sectional analysis.

BACKGROUND: Prior studies suggest that allergist care improves asthma outcomes, but many of these studies have methodological shortcomings. OBJECTIVE: We sought to compare patient-based and medical utilization outcomes in randomly selected asthmatic patients cared for by allergists versus primary care providers. METHODS: A random sample of 3568 patients enrolled in a staff model health maintenance organization who were given diagnoses of persistent asthma completed surveys. Of these participants, 1679 (47.1%) identified a primary care provider as their regular source of asthma care, 884 (24.8%) identified an allergist, 693 (19.4%) reported no regular source of asthma care, and 195 (5.5%) identified a pulmonologist. Validated quality of life, control, severity, patient satisfaction, and self-management knowledge tools and linked administrative data that captured medication use were compared between groups, adjusting for demographics and baseline hospital and corticosteroid use. RESULTS: Compared with those followed by primary care providers, patients of allergists reported significantly higher (P < .001) generic physical and asthma-specific quality of life, less asthma control problems, less severe symptoms, higher satisfaction with care, and greater self-management knowledge. Patients of allergists were less likely than patients of primary care providers to require an asthma hospitalization (odds ratio, 0.45) or unscheduled visit (odds ratio, 0.71) and to overuse beta-agonists (odds ratio, 0.47) and were more likely to receive inhaled steroids (odds ratio, 1.81) during their past year. CONCLUSIONS: Allergist care is associated with a wide range of improved outcomes in asthmatic patients compared with care provided by primary care providers.

Asthma quality-of-care markers using administrative data.

STUDY OBJECTIVE: To evaluate the relationship of potential asthma quality-of-care markers to subsequent emergency hospital care. DESIGN: Retrospective administrative database analysis. SETTING: Managed care organization. PATIENTS: Asthmatic patients aged 5 to 56 years of age. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Candidate quality measures included one or more or four or more controller medication canisters, a controller/total asthma medication ratio of > or = 0.3 or > or = 0.5, and the dispensing of fewer than six beta-agonist canisters in 2002. Outcome was a 2003 asthma emergency department visit or hospitalization. Multivariable analyses adjusted for age, sex, and year 2002 severity (based on utilization). In the total sample (n = 109,774), one or more controllers (odds ratio, 1.35) and four or more controllers (odds ratio, 1.98) were associated with an increased risk of emergency hospital care, whereas a controller/total asthma medication ratio of > or = 0.5 (odds ratio, 0.73) and the dispensing of fewer than six beta-agonist canisters (odds ratio 0.30) were associated with a decreased risk. After adjustment for baseline severity in the total asthma sample, the controller/total asthma medication ratio (odds ratio, 0.62 to 0.78) and beta-agonist measure (odds ratio, 0.42) were associated with decreased risk, whereas the dispensing of four or more canisters of controller medication was associated with increased risk (odds ratio, 1.33). After stratification by year 2002 beta-agonist use, all of the measures were associated with decreased risk in those who received fewer than six beta-agonist canisters, whereas all of the measures except the medication ratio of > or = 0.5 were associated with increased risk in the cohort who received six or more beta-agonist canisters. CONCLUSION: Controller use and beta-agonist use may function as severity indicators in large populations rather than as asthma quality-of-care markers. A medication ratio of > or = 0.5 appeared to function as the best quality-of-care marker in this study.

How well do the HEDIS asthma inclusion criteria identify persistent asthma?

OBJECTIVES: (1) To determine if the Health Plan Employer Data and Information Set (HEDIS) asthma inclusion criteria consistently identify persistent asthma on a year-to-year basis and (2) to explore whether variation in the number of years of qualification is associated with medication and resource utilization outcomes. STUDY DESIGN: Retrospective observational study. METHODS: We identified 132 414 patients in a large healthcare program who were included in 1 or more HEDIS persistent asthma cohorts between 1999 and 2002 and who had continuous insurance and pharmacy benefit coverage for the entire 4-year observation period. Medication, emergency department, and hospital use in 2002 was identified using electronic claims and pharmacy information. RESULTS: Overall, 47.9% of the patients were identified as having persistent asthma in only 1 of 4 years, 40.8% had at least 2 consecutive years, and 28.2% had at least 3 consecutive years. In bivariate and multivariate analyses, more consecutive years of HEDIS persistent asthma qualification significantly increased the likelihood of frequent short-acting b-agonist use, inhaled antiinflammatory corticosteroid use, at least 1 emergency department visit, and at least 1 hospitalization. The strongest relationship was for 3 or more consecutive years of HEDIS qualification. CONCLUSIONS: A significant portion of the HEDIS persistent asthma cohort does not qualify on a year-to-year basis, suggesting that the current 1-year qualification period or the underlying administrative case definition for persistent asthma may be suboptimal. Further clinical validation studies are needed to determine the optimal criteria for a more useful HEDIS persistent asthma case definition.

Relationships among quality of life, severity, and control measures in asthma: an evaluation using factor analysis.

BACKGROUND: Validated psychometric tools measuring quality of life, asthma control, and asthma severity have been developed, but their relationships with each other and with other important patient-centered outcomes have not been rigorously assessed. OBJECTIVE: To use factor analysis to evaluate the relationships of these validated tools with each other and with other patient-centered outcomes. METHODS: Surveys were completed by a random sample of 2854 Health Maintenance Organization members age 18 to 56 years with persistent asthma. Surveys included demographic information; validated tools measuring generic (Short Form-12; SF-12) and asthma-specific (Juniper Mini Asthma Quality of Life Questionnaire; AQLQ) quality of life, asthma control (Asthma Therapy Assessment Questionnaire), and asthma symptom severity (Asthma Outcomes Monitoring System); self-described severity, control, and course over time; and history of acute exacerbations. RESULTS: Principal component analysis suggested a 5-factor model that accounted for approximately 59% of the variability. The most prominent rotated factor reflected asthma symptom frequency (19.4% of variability), was measured by the symptom subscale of the AQLQ, and was the only factor significantly related to the Asthma Therapy Assessment Questionnaire, Asthma Outcomes Monitoring System, or the self-reported assessments of severity, control, or course. Other factors included symptom bother (12.1% of variability), reflected by the environment and emotion AQLQ subscales; activity limitation (13.9% of variability), reflected by the activity AQLQ subscale and the SF-12 physical component scale; mental health (8.3% of variability), reflected by the SF-12 mental component scale; and acute exacerbations (5.0% of variability), not measured by any of the validated scales. CONCLUSION: Distinct components of patient-reported asthma health status can be identified by factor analysis. Distinct constructs of severity versus control cannot be identified by the use of these tools alone.

Relationship of validated psychometric tools to subsequent medical utilization for asthma.

BACKGROUND: Risk stratification is used to identify patients with asthma at increased risk of experiencing morbidity and resource utilization. Validated psychometric tools are infrequently studied sources of data for this purpose. PURPOSE: To evaluate 4 types of validated psychometric tools as predictors for subsequent asthma utilization and determine their clinical usefulness. METHODS: Eleven hundred patients with active asthma from a Health Maintenance Organization completed surveys that included demographic information and validated psychometric tools measuring generic quality of life (physical and mental components), asthma-specific quality of life, asthma control, and asthma symptom severity. Survey records were linked to administrative data that captured emergency department and hospital care, short-acting beta-agonist, and oral corticosteroid utilization for the year of and the year following the survey. Relationships of survey variables with subsequent utilization were assessed, adjusting for both baseline demographic and asthma utilization factors. RESULTS: Scores of each psychometric tool were significantly related to subsequent utilization in univariate analyses and after adjusting for baseline utilization and demographic risk factors. Patients with higher scale-defined morbidity were as much as 4 times more likely to have subsequent utilization (sensitivity as high as 58%; specificity as high as 78%). Addition of an asthma-specific tool to either demographic or utilization prediction models added sensitivity (as much as 15%) but did not substantially improve the prediction properties of models containing both demographic and utilization predictors. CONCLUSION: Validated psychometric tools appear useful for asthma risk stratification in individuals and in populations in which both utilization and demographic predictors are not available.