Rachael L. DiSantostefano

Risk of Pneumonia with Inhaled Corticosteroid versus Long-Acting Bronchodilator Regimens in Chronic Obstructive Pulmonary Disease: A New-User Cohort Study

Introduction Observational studies using case-control designs have showed an increased risk of pneumonia associated with inhaled corticosteroid (ICS)-containing medications in patients with chronic obstructive pulmonary disease (COPD). New-user observational cohort designs may minimize biases associated with previous case-control designs. Objective To estimate the association between ICS and pneumonia among new users of ICS relative to inhaled long-acting bronchodilator (LABD) monotherapy. Methods Pneumonia events in COPD patients ≥45 years old were compared among new users of ICS medications (nu200a=u200a11,555; ICS, ICS/long-acting β2-agonist [LABA] combination) and inhaled LABD monotherapies (nu200a=u200a6,492; LABA, long-acting muscarinic antagonists) using Cox proportional hazards models, with propensity scores to adjust for confounding. Setting: United Kingdom electronic medical records with linked hospitalization and mortality data (2002–2010). New users were censored at earliest of: pneumonia event, death, changing/discontinuing treatment, or end of follow-up. Outcomes: severe pneumonia (primary) and any pneumonia (secondary). Results Following adjustment, new use of ICS-containing medications was associated with an increased risk of pneumonia hospitalization (nu200a=u200a322 events; HRu200a=u200a1.55, 95% CI: 1.14, 2.10) and any pneumonia (nu200a=u200a702 events; HRu200a=u200a1.49, 95% CI: 1.22, 1.83). Crude incidence rates of any pneumonia were 48.7 and 30.9 per 1000 person years among the ICS-containing and LABD cohorts, respectively. Excess risk of pneumonia with ICS was reduced when requiring ≥1 month or ≥ 6 months of new use. There was an apparent dose-related effect, with greater risk at higher daily doses of ICS. There was evidence of channeling bias, with more severe patients prescribed ICS, for which the analysis may not have completely adjusted. Conclusions The results of this new-user cohort study are consistent with published findings; ICS were associated with a 20–50% increased risk of pneumonia in COPD, which reduced with exposure time. This risk must be weighed against the benefits when prescribing ICS to patients with COPD.

Which patients with chronic obstructive pulmonary disease benefit from the addition of an inhaled corticosteroid to their bronchodilator? A cluster analysis

Objective To identify subsets of chronic obstructive pulmonary disease (COPD) patients who are more protected from exacerbations with the use of an inhaled corticosteroid/long-acting β2 agonist (ICS/LABA) combination, compared with the use of LABA monotherapy. Design Post hoc cluster analysis of patients from two randomised clinical trials of salmeterol/fluticasone propionate (SFC) and salmeterol (SAL) that had primary endpoints of moderate/severe exacerbation rates. Setting Centres in North America. Participants 1543 COPD patients were studied. Interventions SFC 50/250u2005µg or SAL 50u2005µg, twice daily. Primary and secondary outcome measures The analysis identified clusters of COPD patients more responsive to SFC versus SAL with respect to the annual rate of moderate/severe exacerbations and compared their baseline clinical characteristics. Results Overall, SFC significantly reduced the annual rate of moderate/severe exacerbations as compared with SAL alone (rate ratio (RR)=0.701, p<0.001). Three-patient clusters were identified: COPD patients receiving diuretics (RR=0.56, p<0.001); patients not receiving diuretics but with forced expiratory volume in 1 s (FEV1) reversibility ≥12% (RR=0.67, p<0.001) exhibited a substantial reduction in the annual rate of moderate/severe exacerbations relative to SAL. A third cluster, consisting of patients not receiving diuretics and without FEV1 reversibility, demonstrated no difference for SFC versus SAL. Patients receiving diuretics had a significantly higher prevalence of comorbid cardiovascular disease. Conclusions COPD patients receiving diuretics and those not receiving diuretics but with FEV1 reversibility >12% at baseline were significantly more likely to experience a reduction in COPD-associated exacerbations with SFC versus SAL alone. Trial registration NCT00115492, NCT00144911

Ecologic analysis of asthma-related events and dispensing of inhaled corticosteroid- and salmeterol-containing products

BACKGROUNDnAn association between salmeterol use and serious asthma episodes or asthma-related mortality has been noted in 2 clinical trials; however, a causal relationship has not been established. To date, observational studies have not replicated this finding.nnnOBJECTIVEnTo examine the relationship between number of prescriptions dispensed of salmeterol-containing products and inhaled corticosteroid (ICS)-containing products and the rates of asthma-related hospitalizations and mortality in the United States.nnnMETHODSnIn this ecologic study, annual age-adjusted rates of asthma-related hospitalization and asthma-related mortality from US population-based sources were graphed alongside annual number of prescriptions dispensed of salmeterol- and ICS-containing products by year from 1991 to 2004. We computed the Spearman rank correlations between number of prescriptions dispensed and serious events (asthma-related hospitalization rate, number of hospitalizations, asthma-related mortality rate, and number of asthma deaths).nnnRESULTSnDuring more than 14 years, while number of prescriptions dispensed of salmeterol-containing and ICS-containing products increased, age-adjusted asthma-related mortality rates declined and asthma-related hospitalization rates remained relatively stable. The number of asthma-related deaths has decreased steadily since the mid-1990s.nnnCONCLUSIONnThis study provides population-level evidence that asthma-related death rates declined and asthma-related hospitalization rates remained relatively constant for more than 14 years during a period of improvements in asthma management per treatment guidelines, including increased use of maintenance medications, such as ICSs and salmeterol.

Relationship between blood eosinophils and clinical characteristics in a cross-sectional study of a US population-based COPD cohort

BACKGROUNDnCurrent evidence suggests that blood eosinophil levels (Eos) are associated with chronic obstructive pulmonary disease (COPD) treatment response and natural history. This analysis investigated the relationship between Eos levels and clinical characteristics in a representative cohort of US subjects with spirometry-defined COPD.nnnMETHODSnCross-sectional data from the National Health And Nutrition Examination Survey (NHANES 2007-2010) of subjects ≥ 40 years with spirometry-defined COPD and Eos data (n = 948) were analyzed. Differences in clinical characteristics by Eos level (≤ 2%, > 2%) were compared using chi-square tests. Characteristics associated with Eos > 2% were identified using multivariate logistic regression modeling. Characteristics associated with Eos >2% among subjects with normal lung function, plus other cut-points among the COPD population, were evaluated post hoc.nnnFINDINGSnMost participants had Eos >2%; 70.7% with spirometry-defined COPD and 65.5% with normal lung function. Older age, male gender, and severe current asthma were significantly associated with Eos >2% in COPD subjects. The Eos ≤ 2% COPD group had higher reported rates of previous heart attack and anemia. Among participants with normal lung function, Eos > 2% was associated with being male, being overweight/obese, older age, hay fever, and congestive heart failure.nnnINTERPRETATIONnIn this large US-based cohort, Eos > 2% was prevalent in participants with COPD and normal lung function. Among participants with COPD, Eos > 2% was associated with specific characteristics including lower rates of some co-morbidities; however, the clinical implications and relationships between Eos levels, COPD mechanisms, and risk of outcomes require further evaluation.

Identification of responders to inhaled corticosteroids in a chronic obstructive pulmonary disease population using cluster analysis

Objectives To identify clusters of patients who may benefit from treatment with an inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA) versus LABA alone, in terms of exacerbation reduction, and to validate previously identified clusters of patients with chronic obstructive pulmonary disease (COPD) (based on diuretic use and reversibility). Design Post hoc supervised cluster analysis using a modified recursive partitioning algorithm of two 1-year randomised, controlled trials of fluticasone furoate (FF)/vilanterol (VI) versus VI alone, with the primary end points of the annual rate of moderate-to-severe exacerbations. Setting Global. Participants 3255 patients with COPD (intent-to-treat populations) with a history of exacerbations in the past year. Interventions FF/VI 50/25u2005µg, 100/25u2005µg or 200/25u2005µg, or VI 25u2005µg; all one time per day. Outcome measures Mean annual COPD exacerbation rate to identify clusters of patients who benefit from adding an ICS (FF) to VI bronchodilator therapy. Results Three clusters were identified, including two groups that benefit from FF/VI versus VI: patients with blood eosinophils >2.4% (RR=0.68, 95% CI 0.58 to 0.79), or blood eosinophils ≤2.4% and smoking history ≤46 pack-years, experienced a reduced rate of exacerbations with FF/VI versus VI (RR=0.78, 95% CI 0.63 to 0.96), whereas those with blood eosinophils ≤2.4% and smoking history >46 pack-years were identified as non-responders (RR=1.22, 95% CI 0.94 to 1.58). Clusters of patients previously identified in the fluticasone propionate/salmeterol (SAL) versus SAL trials of similar design were not validated; all clusters of patients tended to benefit from FF/VI versus VI alone irrespective of diuretic use and reversibility. Conclusions In patients with COPD with a history of exacerbations, those with greater blood eosinophils or a lower smoking history may benefit more from ICS/LABA versus LABA alone as measured by a reduced rate of exacerbations. In terms of eosinophils, this finding is consistent with findings from other studies; however, the validity of the 2.4% cut-off and the impact of smoking history require further investigation. Trial registration numbers NCT01009463; NCT01017952; Post-results.

Chronic respiratory disease, comorbid cardiovascular disease and mortality in a representative adult US cohort

We sought to determine the relationship between chronic respiratory disease, cardiovascular disease (CVD) and mortality in a nationally representative cohort of the US population aged 40 years and older.

An evaluation of asthma medication utilization for risk evaluation and mitigation strategies (REMS) in the United States: 2005–2011

Abstract Purpose: The purpose of this study was to assess drug utilization patterns of fluticasone propionate (FP)/salmeterol (SAL) combination (FSC) and SAL over the 7-year period of 2005–2011 in patients with asthma as part of the Risk Evaluation and Mitigation Strategies (REMS). Methods: A descriptive, retrospective observational study utilizing national pharmacy data and employer-based claims data to characterize drug utilization patterns. Results: For patients with asthma, the total number of FSC and SAL dispensings and users of FSC and SAL has declined between 2005 and 2011. During this period, FSC and SAL dispensing for asthma decreased 24% and 76%, respectively, with a more pronounced decline between 2010 and 2011 relative to other years. The total number of patients with asthma who were dispensed FSC has decreased by 10% among adults and by 40% in children and adolescents. While SAL-containing medications decreased, dispensing of FP monotherapy increased 39% during the same 7-year period. The number of patients dispensed FP for asthma has increased 47% in children 4–11 years of age, 72% in adolescents 12–17 years of age, and 6% in adults. SAL use without a controller was infrequent and decreasing, reported by 1.7% and 0.5% of patients with asthma in 2005 and 2011, respectively. Conclusions: In patients with asthma, use of FSC and SAL decreased between 2005 and 2011, while the use of FP increased. Use of SAL monotherapy was infrequent and declined during the study period. The data suggest that the substantial communication activities have encouraged appropriate prescribing of long-acting β2-adrenergic agonist (LABA).

Prescription Patterns in Asthma Patients Initiating Salmeterol in UK General Practice: A Retrospective Cohort Study using the General Practice Research Database (GPRD)

AbstractBackground: An association between salmeterol, a long-acting β2-agonist (LABA), use and rare serious asthma events or asthma mortality was observed in two large clinical trials. This has resulted in heightened scrutiny of LABAs and comprehensive reviews by regulatory agencies.n Objective: The aim of this retrospective observational cohort study was to better characterize salmeterol medication use patterns in the UK. We describe asthma prescription patterns in a cohort of patients (n = 17 745) in the General Practice Research Database who initiated treatment with salmeterol-containing prescriptions between 2003 and 2006, including salmeterol and salmeterol/fluticasone propionate in a single device.n Methods: Prescriptions patterns by medication class, including concurrent prescription of salmeterol with inhaled corticosteroids (ICS), were described using 6-month intervals in the 1-year period before and after the salmeterol-containing index prescription.n Results: In the 0- to 6-month and 7- to 12-month periods prior to initiation of the salmeterol-containing prescription, the cohort experienced worsening of asthma, measured by an increase in the proportion of patients with prescriptions for short-acting β-agonists [SABA] (73–89%), ICS (70–81%) and systemic corticosteroids (14–28%). Nearly all patients prescribed salmeterol were concurrently prescribed ICS (≥95% within 90 days). In the 12 months following initiation of the salmeterol-containing prescription, a decrease in asthma prescriptions was observed.n Discussion: These results support the appropriate prescribing of salmeterol-containing medications, as per recommendations in asthma treatment guidelines in the UK.n Conclusion: Salmeterol was consistently prescribed as an add-on asthma-controller with an ICS for most patients, and was associated with improvements in asthma control, as indicated by decreases in SABA and systemic corticosteroid prescriptions following salmeterol introduction.

Patient Comprehension of Medication Guides for Asthma and Chronic Obstructive Pulmonary Disease Medications

Purpose: This study assessed patients’ comprehension of the Advair and Serevent medication guides (MGs) and MG reading behaviors with the goal to improve risk communication. Methods: After reading their assigned MGs, 452 adults with asthma or chronic obstructive pulmonary disease participated in structured interviews to assess comprehension of safety risks in the Advair MG (asthma, n = 150; chronic obstructive pulmonary disease, n = 153) and Serevent MG (asthma, n = 149). Generalized estimating equations for correlated binary data were used to identify factors associated with correct responses. Results: For 10 of 12 individual risk questions, ≥75% of patients reported correct responses. After adjusting for patient characteristics, health literacy was significantly associated with correct responses (odds ratio = 1.03, 95% confidence interval = 1.02-1.05 per 1-point increase in the Rapid Estimate of Adult Literacy in Medicine). MG reading behaviors were inconsistent, with many patients reading MGs only once (40%) despite multiple prescriptions. Conclusions: Comprehension of safety risks in the Advair and Serevent MGs was adequate for most patients in the study but decreased with health literacy. Initiatives to improve patient-directed risk communication should consider health literacy and reasons for inconsistent reading behaviors.

Medication Guide Reading Behaviors and Attitudes Among Subjects With Migraine, Asthma, or COPD

Background: This cross-sectional survey describes attitudes and reading behaviors toward medication guides among 785 subjects with migraine, asthma, or COPD who reported recent use of Treximet (sumatriptan/naproxen sodium) or Advair (fluticasone propionate/salmeterol). Results: The survey demonstrated that the majority (82%) of subjects had read their medication guide, but most read it exactly once and did not read it thoroughly. Patients did not read medication guides with each refill, with the most frequent reasons being that they did not expect the information to have changed and that a doctor would tell them what they needed to know. Factors significantly associated with patients hypothetically being more likely to read medication guides associated with their new prescription included increasing age, simplification to format and content of the medication guide, and where subjects typically received their medication safety information. Patients reported acquiring medication safety from doctors or pharmacists more frequently than from medication guides. Conclusions: The results provide insights into potential revisions to the medication guides that may improve reading behaviors.