Frank Albers

Cluster analysis and characterization of response to mepolizumab. A step closer to personalized medicine for patients with severe asthma.

RATIONALE Detailed characterization of asthma phenotypes is essential for identification of responder populations to allow directed personalized medical intervention. OBJECTIVES The aim of this study was to identify distinctive patient characteristics within subgroups of a well-characterized severe asthma population at risk for exacerbations and to determine the treatment response within each subgroup. METHODS A supervised cluster analysis with recursive partitioning approach was applied to data from the Dose Ranging Efficacy And safety with Mepolizumab (DREAM) study to identify characteristics that maximized the differences across subgroups. Exacerbation rate ratios were calculated for each cluster comparing mepolizumab versus placebo. MEASUREMENTS AND MAIN RESULTS Three predictors were identified in four primary clusters: blood eosinophils, airway reversibility, and body mass index. The reduction in exacerbations was significantly greater in patients who received mepolizumab (clusters 2, 3, and 4) with raised eosinophils (responder population). Cluster 2 with low airway reversibility (mean, 11%) had a 53% reduction in exacerbations. These patients more frequently reported sinusitis and nasal polyposis. Those with higher airway reversibility (mean, 28%) were further split by body mass index. The nonobese versus obese (clusters 3 and 4) had a 35 and 67% reduction in exacerbations, respectively. Cluster 4 also had patients with more comorbidities, including hypertension, weight gain, and anxiety. CONCLUSIONS Using supervised cluster analysis helped identify specific patient characteristics related to disease and therapeutic response. Patients with eosinophilic inflammation received significant therapeutic benefit with mepolizumab, and responses differed within clusters. Clinical trial registered with www.clinicaltrials.gov (NCT01000506).

Effects of Tiotropium on Hyperinflation and Treadmill Exercise Tolerance in Mild to Moderate Chronic Obstructive Pulmonary Disease

RATIONALE Bronchodilator therapy represents a potentially valuable therapeutic option to increase exercise tolerance and enhance lung function in mild to moderate chronic obstructive pulmonary disease (COPD). OBJECTIVES To determine effects of tiotropium on pulmonary hyperinflation and exercise tolerance in patients with symptomatic Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 and 2 COPD who experienced inspiratory capacity decrease greater than or equal to 100 ml during incremental and constant work rate treadmill exercise. METHODS This 22-week, randomized, double-blind, two-period crossover study evaluated the efficacy of once-daily tiotropium bromide (18 μg) versus placebo in patients with GOLD 1 and 2 COPD. Primary endpoint was between-group (tiotropium vs. placebo) difference in inspiratory capacity at isotime (i.e., at the time the shortest test ended) during constant work rate treadmill exercise from baseline to the end of a 6-week treatment period. Key secondary endpoints included differences in exercise duration and exertional dyspnea. Safety was assessed by recording adverse events. MEASUREMENTS AND MAIN RESULTS Study population comprised 48 patients with GOLD 1 COPD and 78 patients with GOLD 2 COPD. Resting inspiratory capacity significantly improved with tiotropium versus placebo in the overall (P < 0.0001), GOLD 1 (P = 0.0183), and GOLD 2 (P < 0.0001) groups. Isotime inspiratory capacity was significantly enhanced during exercise in the overall (P = 0.0087) and GOLD 2 (P = 0.0494) groups after tiotropium versus placebo. Tiotropium versus placebo significantly enhanced exercise duration in the GOLD 2 group (P = 0.0070) but not in the GOLD 1 or overall patient groups. In the overall group, increase in exercise duration seen with tiotropium was well correlated with the increase in isotime inspiratory capacity (r = 0.463, P < 0.0001). CONCLUSIONS Resting and exercise hyperinflation were ameliorated by bronchodilator therapy with tiotropium in the overall GOLD 1 plus 2 COPD group. Exercise tolerance was enhanced in GOLD 2, but not GOLD 1, COPD. Clinical trial registered with www.clinicaltrials.gov (NCT01072396).

The Impact of Screening Tools on Diagnosis of Chronic Obstructive Pulmonary Disease in Primary Care

BACKGROUND Chronic obstructive pulmonary disease (COPD) is frequently misdiagnosed or undiagnosed, which can delay disease management interventions. PURPOSE The Screening, Evaluating and Assessing Rate CHanges of diagnosing respiratory conditions in primary care 1 (SEARCH1) study assessed whether screening using the COPD Population Screener (COPD-PS) questionnaire to detect COPD risk factors and symptoms, with or without a handheld spirometer (copd-6) to detect airflow limitation, can increase yields of COPD diagnosis and respiratory-related clinician actions in primary care. DESIGN A prospective, multi-center, pragmatic, comparative-effectiveness, cluster-randomized study conducted from September 2010 to October 2011 (data analyzed from December 2011 to January 2013). PARTICIPANTS Men and women aged ≥40 years visiting their participating primary care practice for any reason. INTERVENTION Practices were randomized to three study arms: COPD-PS + copd-6, COPD-PS alone, and usual care (no interventions). No practices received any specific education about COPD or its diagnosis. MAIN OUTCOME MEASURES The primary endpoint was yield of new clinical COPD diagnosis; the secondary endpoint was yield of respiratory-related clinician actions. RESULTS Of 9,704 patients enrolled, 8,770 had no prior COPD diagnosis and were included in endpoint analyses. Both interventions significantly increased COPD diagnostic yield over 8 weeks. Compared with a mean yield of 0.49% (0.13%) (controls), yields were 1.07% (0.20%) (OR=2.20, 95% CI=1.26, 3.84, p=0.006) and 1.16% (0.22%) (OR=2.38, 95% CI=1.38, 4.13, p=0.002) for COPD-PS and COPD-PS+copd-6 study arms, respectively. Respiratory-related clinician actions were not significantly different across study arms. CONCLUSIONS Office-based assessment can significantly increase COPD diagnosis by primary care physicians. Future trials must evaluate whether screening can improve outcomes for patients with COPD.

The Continuum of Physiological Impairment during Treadmill Walking in Patients with Mild-to-Moderate COPD: Patient Characterization Phase of a Randomized Clinical Trial

Background To have a better understanding of the mechanisms of exercise limitation in mild-to-moderate chronic obstructive pulmonary disease (COPD), we compared detailed respiratory physiology in patients with COPD and healthy age- and sex-matched controls. Methods Data were collected during the pre-treatment, patient characterization phase of a multicenter, randomized, double-blind, crossover study. Patients with COPD met Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 or 2 spirometric criteria, were symptomatic, and had evidence of gas trapping during exercise. All participants completed pulmonary function and symptom-limited incremental treadmill exercise tests. Results Chronic activity-related dyspnea measured by Baseline Dyspnea Index was similarly increased in patients with GOLD 1 (n = 41) and 2 (n = 63) COPD compared with controls (n = 104). Plethysmographic lung volumes were increased and lung diffusing capacity was decreased in both GOLD groups. Peak oxygen uptake and work rate were reduced in both GOLD groups compared with controls (p<0.001). Submaximal ventilation, dyspnea, and leg discomfort ratings were higher for a given work rate in both GOLD groups compared with controls. Resting inspiratory capacity, peak ventilation, and tidal volume were reduced in patients with GOLD 2 COPD compared with patients with GOLD 1 COPD and controls (p<0.001). Conclusions Lower exercise tolerance in patients with GOLD 1 and 2 COPD compared with controls was explained by greater mechanical abnormalities, greater ventilatory requirements, and increased subjective discomfort. Lower resting inspiratory capacity in patients with GOLD 2 COPD was associated with greater mechanical constraints and lower peak ventilation compared with patients with GOLD 1 COPD and controls. Trial Registration ClinicalTrials.gov: NCT01072396

Economic Burden of Illness Among Patients with Severe Asthma in a Managed Care Setting

BACKGROUND Despite intensive pharmacotherapy, a considerable number of patients with severe asthma have inadequate disease control. Patients with severe asthma who experience exacerbations consume significant health care resources. OBJECTIVE To assess health care resource utilization and associated costs among patients with persistent severe asthma who experienced exacerbations compared with patients with persistent but nonsevere asthma. METHODS This retrospective analysis of a national administrative claims database identified patients aged ≥ 12 years who had at least 1 medical claim with an asthma diagnosis in 2012 and had continuous medical and pharmacy coverage under a commercial or Medicare Advantage plan from January 1, 2012, to December 31, 2013. Patients were assigned to 1 of 2 mutually exclusive cohorts-persistent asthma (PA) or severe asthma (SA)-according to an established algorithm based on asthma-related health care resource use and pharmacy claims for controller medication. SA patients were required to meet PA criteria and also have evidence of ≥2 asthma exacerbations in 2012. Asthma-related health care resource utilization and costs were computed from asthma medication use (rescue and controller therapy) and medical claims with an asthma diagnosis in the primary position in 2012 and 2013. Adherence to controller therapy was assessed over 365 days by using the proportion of days covered (PDC), starting with the first claim for controller therapy in 2012. Differences between the PA and SA cohorts were analyzed by t-test for continuous variables and chi-square test for categorical variables. Asthma-related costs in 2013 were also analyzed using a generalized linear model with a gamma distribution and log link, adjusted for patient demographics (age, gender, region, and insurance type) and Quan-Charlson comorbidity score. RESULTS A total of 65,359 patients were included: 63,597 (97.3%) PA patients and 1,762 SA patients (2.7%). Compared with the PA cohort, the SA cohort was older (mean age = 50.8 years vs. 46.5 years, P < 0.001) and had higher mean comorbidity score (1.47 vs. 1.31, P< 0.001). The mean count of all asthma medications fills was 2.2-fold (2012) and 2.1-fold (2013) higher in the SA cohort, compared with the PA cohort (P< 0.001). Mean PDC for all oral and inhaled controller therapy was also higher in the SA cohort compared with the PA cohort (0.80 vs. 0.65, P< 0.001). SA patients had a significantly greater mean count of asthma-related hospitalizations, emergency room visits, and ambulatory visits in 2012 and 2013 (P< 0.001). Unadjusted mean annual asthma-related costs in the SA versus PA cohorts were

Design, rationale, and baseline demographics of SEARCH I: a prospective cluster-randomized study.

6,496 versus

Characteristics of adult onset vs. late onset asthma - a multinational database cohort study

2,739 (P < 0.001) in 2012 and

Predictors of respiratory health status in patients with severe asthma

5,174 versus

Clinical characteristics and burden of illness in a cohort of severe asthma patients

1,775 (P< 0.001) in 2013. Higher asthma-related costs were driven by greater mean annual asthma medication costs in 2012 (

Lung Function And Exercise Impairment In Patients With GOLD Stage I And II COPD

4,545 vs.