Omalizumab Effectiveness by Biomarker Status in Patients with Asthma: Evidence From PROSPERO, A Prospective Real-World Study.

BACKGROUND: Omalizumab has demonstrated efficacy in clinical trials of patients with asthma, but real-world data are needed. OBJECTIVE: To assess outcomes after omalizumab initiation in patients with asthma in a real-world setting. METHODS: Patients aged 12 years and older with allergic asthma who were candidates for omalizumab on the basis of physician-assessed need were enrolled in a US-based, prospective, single-arm, 48-week multicenter study, the Prospective Observational Study to Evaluate Predictors of Clinical Effectiveness in Response to Omalizumab. Monthly assessments included exacerbations, health care utilization, asthma control test (ACT), and adverse events. At baseline, 6 months, and end of study, biomarkers (blood eosinophils and fractional exhaled nitric oxide) were collected and spirometry performed. RESULTS: Of 806 enrollees, 801 (99.4%) received omalizumab and 622 (77.2%) completed the study. The exacerbation rate significantly improved from a mean of 3.00 ± 3.28 in the 12 months before baseline to 0.78 ± 1.37 through month 12 (P < .001) and was similar in adults and adolescents; there was a reduction of 81.9% in the percentage of patients with 1 or more hospitalizations. Lung function remained generally unchanged. A mean improvement of 4.4 ± 4.9 in ACT scores was observed. Eighty-seven percent of patients were responders on the basis of clinical improvement in exacerbations, lung function, or ACT scores. Baseline biomarker status was associated with ACT scores and lung function improvement, but the magnitude of this improvement was not clinically relevant. No new safety signals emerged. CONCLUSIONS: Omalizumab initiation in patients with asthma resulted in improved exacerbation rates, reduced hospitalizations, and improved ACT scores compared with pretreatment values, regardless of biomarker status.

Asthma Exacerbations and Triggers in Children in TENOR: Impact on Quality of Life.

BACKGROUND: Data examining associations between asthma exacerbations, triggers, and asthma-related quality of life (QOL) in children with severe/difficult-to-treat asthma are unavailable. OBJECTIVE: To evaluate real-world data on relationships between asthma exacerbations, triggers, and QOL in children using data from TENOR (The Epidemiology and Natural History of Asthma Outcomes and Treatment Regimens), a 3-year observational study of patients with severe/difficult-to-treat asthma, including those aged 6 to 12 years. METHODS: QOL was examined using the Pediatric Asthma Quality of Life Questionnaire (PAQLQ) and defined exacerbations hierarchically (descending order of severity): hospitalization, emergency department visit, steroid burst, no exacerbation, using the highest value from months 6 and 12. One-way ANOVA was used to test for differences in PAQLQ domain scores at month 12 across exacerbation severity, total number of asthma exacerbations, and number of baseline asthma triggers. Mantel-Haenszel chi-square test was used to test the association between the number of triggers and exacerbation hierarchy. RESULTS: Greater severity of asthma exacerbations was associated with significantly (P < .001) lower mean PAQLQ domain scores, indicating poorer QOL. A higher number of asthma exacerbations was associated with significantly (P < .001) lower mean PAQLQ domain scores. PAQLQ scores were significantly lower with higher numbers of baseline triggers. Higher baseline number of asthma triggers was associated with greater severity (P = .05) and number of asthma exacerbations (P < .001). CONCLUSIONS: A higher number of asthma triggers at baseline was associated with greater asthma severity and number of asthma exacerbations and lower QOL in children with severe/difficult-to-treat asthma.

Baseline asthma burden, comorbidities, and biomarkers in omalizumab-treated patients in PROSPERO.

BACKGROUND: Patients included in clinical trials do not necessarily reflect the real-world population. OBJECTIVE: To understand the characteristics, including disease and comorbidity burden, of patients with asthma receiving omalizumab in a real-world setting. METHODS: The Prospective Observational Study to Evaluate Predictors of Clinical Effectiveness in Response to Omalizumab (PROSPERO) was a US-based, multicenter, single-arm, and prospective study. Patients (≥12 years of age) with allergic asthma initiating omalizumab treatment based on physician-assessed need were included and followed for 12 months. Exacerbations, health care use, adverse events, and Asthma Control Test (ACT) scores were assessed monthly. Biomarkers (blood eosinophils, fractional exhaled nitric oxide, and periostin) were evaluated and patient-reported outcomes (Asthma Quality of Life Questionnaire for 12 Years and Older [AQLQ+12] and Work Productivity and Activity Impairment: Asthma questionnaire [WPAI:Asthma]) were completed at baseline and months 6 and 12. The Mini Rhinoconjunctivitis Quality of Life Questionnaire (MiniRQLQ) was completed at baseline and 12 months. RESULTS: Most of the 806 enrollees (91.4%) were adults (mean age 47.3 years, SD 17.4), white (70.3%), and female (63.5%). Allergic comorbidity was frequently reported (84.2%), as were hypertension (35.5%) and depression (22.1%). In the 12 months before study entry, 22.1% of patients reported at least 1 asthma-related hospitalization, 60.7% reported at least 2 exacerbations, and 83.3% reported ACT scores no higher than 19 (uncontrolled asthma). Most patients had low biomarker levels based on prespecified cut-points. Baseline mean patient-reported outcome scores were 4.0 (SD 1.4) for AQLQ+12, 2.7 (SD 1.4) for MiniRQLQ, and 47.7 (SD 28.9) for WPAI:Asthma percentage of activity impairment and 33.5 (SD 28.7) for percentage of overall work impairment. CONCLUSION: The population initiating omalizumab in PROSPERO reported poorly controlled asthma and a substantial disease burden. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01922037.

Patient Outcomes, Health Care Resource Use, and Costs Associated with High Versus Low HEDIS Asthma Medication Ratio.

BACKGROUND: The Healthcare Effectiveness Data and Information Set (HEDIS) quality measures for asthma include the asthma medication ratio (AMR) as a marker of quality of care for patients with asthma. Few data are available to describe the association between health care use and costs in patients with high versus low AMR. OBJECTIVE: To characterize health care use and costs associated with high versus low AMR in patients participating in commercial health plans. METHODS: In a commercial claims database, this study retrospectively identified patients aged 5 to 64 years on December 31, 2011, who met the HEDIS definition of asthma in the premeasurement year (January 1, 2010-December 31, 2010) and the measurement year (January 1, 2011-December 31, 2011). Each patient was classified as having either high or low AMR based on the HEDIS definition. AMR was calculated as the ratio of controller to total asthma medications; high AMR was defined as ≥ 0.5. Annual per-patient health care use and costs were compared in patients with high versus low AMR using (a) multivariable linear regression models to estimate mean annual number of office visits, oral corticosteroids (OCS) bursts (≤ 15-day supply), and costs and (b) negative binomial models to estimate mean annual hospitalization and emergency department (ED) visits. All estimates were adjusted for age, sex, region, and Charlson Comorbidity Index score to control for differences between patients with high versus low AMR. RESULTS: Patients were identified with high (30,575) and low (6,479) AMR. An average patient with high AMR had more all-cause office visits (14.1 vs. 11.0; P < 0.001), fewer all-cause hospitalizations (0.109 vs. 0.215; P < 0.001), fewer all-cause ED visits (0.321 vs. 0.768; P < 0.001), and fewer OCS bursts (0.83 vs. 1.33; P < 0.001) than an average patient with low AMR. An average patient with high AMR had fewer asthma-related hospitalizations (0.024 vs. 0.088; P < 0.001) and ED visits (0.060 vs. 0.304; P < 0.001) than an average patient with low AMR. Numbers of asthma-related annual office visits were similar between the high and low AMR groups (high 2.2 vs. low 2.2; not significant). The rate of poor asthma control events (≥ 6 short-acting beta-agonist dispensing events or ≥ 2 OCS bursts, asthma-related ED visits, or hospitalizations) was greater in patients with low AMR than in patients with high AMR (74.3% vs. 26.9%). An average patient with high AMR had lower annual nonmedication costs than an average patient with low AMR ($5,733 vs. $6,295; P = 0.011). Similar trends emerged for asthma-related costs. A patient with high AMR had higher average total annual health care costs than a patient with low AMR ($9,811 vs. $8,398; P < 0.001). These increased costs primarily resulted from increased medication costs for patients with high versus low AMR ($4,077 vs. $2,103; P < 0.001). CONCLUSIONS: Although patients with high AMR had more office visits and higher medication (which resulted in higher overall health care) costs, their care was marked by fewer OCS bursts (indicating fewer instances of poor asthma control), fewer ED visits, and fewer hospitalizations and lower non-medication costs than those patients with low AMR. These findings support the use of AMR as a care quality measure for patients with persistent asthma. DISCLOSURES: This study was funded by Genentech. Luskin has received consulting and lecture fees, research and travel support, and payment for developing educational presentations from Genentech and has received lecture fees from Merck. Raimundo and Solari are employees of Genentech. Antonova was employed by Genentech at the time of this study. Broder and Chang are employees of Partnership for Health Analytic Research, which received funding from Genentech to conduct this research. Study concept and design were contributed by all authors. Broder and Chang conducted analyses. All authors interpreted the data. Antonova wrote the manuscript with assistance from the other authors. All authors participated in manuscript review and revisions.

Pharmacoeconomics of Biologic Therapy.

Novel biologic agents have allowed clinicians to achieve improved patient outcomes. Appropriate pharmacoceconomic analyses demand evaluation of all relevant costs, including the treatments, the disease and comorbidities, and costs of alternative treatments, including their short- and long-term side effects. Only with complete data can the value of therapies be correctly estimated. By assessing costs, pharmacoeconomic studies complement studies of efficacy and safety, helping to determine the relationships of treatment and outcome. This article provides a broad framework for understanding and evaluating published economic analyses and identifying the key costs and benefits caring for patients with asthma and other immune diseases.

A randomized multicenter study evaluating Xolair persistence of response after long-term therapy.

BACKGROUND: Few data are available to assist clinicians with decisions regarding long-term use of asthma therapies, including omalizumab. OBJECTIVE: We sought to evaluate the benefit and persistence of response in subjects continuing or withdrawing from long-term omalizumab treatment. METHODS: Evaluating the Xolair Persistency Of Response After Long-Term Therapy (XPORT) was a randomized, double-blind, placebo-controlled withdrawal study that included subjects with moderate-to-severe persistent asthma receiving long-term omalizumab. Subjects were randomized by using a hierarchical dynamic randomization scheme to continue their same dose of omalizumab or withdraw to placebo and were then followed every 4 weeks for 1 year. The primary outcome was any protocol-defined severe asthma exacerbation. The secondary outcome was time to first protocol-defined severe asthma exacerbation. Exploratory outcomes included changes in Asthma Control Questionnaire and Asthma Control Test scores. RESULTS: Significantly more subjects in the omalizumab group (67%) had no protocol-defined exacerbation than in the placebo group (47.7%); an absolute difference of 19.3% (95% CI, 5.0%, 33.6%) represents a 40.1% relative difference. Time to first protocol-defined exacerbation analysis revealed a significantly different between-group exacerbation pattern that was consistent with the primary analysis. Subjects continuing omalizumab had significantly better asthma control (mean [SD] change from baseline to week 52: Asthma Control Test score, -1.16 [4.14] vs placebo, -2.88 [5.38], P = .0188; Asthma Control Questionnaire score, 0.22 [0.66] vs placebo, 0.63 [1.13], P = .0039). Discontinuation of omalizumab was associated with an increase in free IgE levels and an increase in basophil expression of the high-affinity IgE receptor. No safety concerns were noted. CONCLUSION: Continuation of omalizumab after long-term treatment results in continued benefit, as evidenced by improved symptom control and reduced exacerbation risk.

Health care resource use and costs associated with possible side effects of high oral corticosteroid use in asthma: a claims-based analysis.

BACKGROUND: The objective of this study was to estimate the prevalence of possible oral corticosteroid (OCS)-related side effects and health care resource use and costs in patients with asthma. METHODS: This was a cross-sectional, matched-cohort, retrospective study using a commercial claims database. Adults with asthma diagnosis codes and evidence of asthma medication use were studied. Patients with high OCS use (≥30 days of OCS annually) were divided into those who did versus those who did not experience OCS-related possible side effects. Their health care resource use and costs were compared using linear regression or negative binomial regression models, adjusting for age, sex, geographic region, Charlson Comorbidity Index score, and chronic obstructive pulmonary disease status. RESULTS: After adjustment, high OCS users with possible side effects were more likely to have office visits (23.0 vs 19.6; P<0.001) and hospitalizations (0.44 vs 0.22; P<0.001) than those without possible side effects. Emergency department visits were similar between the groups. High OCS users with possible side effects had higher adjusted total annual mean health care costs ($25,168) than those without such side effects ($21,882; P=0.009). CONCLUSION: Among high OCS users, patients with possible OCS-related side effects are more likely to use health care services than those without such side effects. Although OCS may help control asthma and manage exacerbations, OCS side effects may result in additional health care resource use and costs, highlighting the need for OCS-sparing asthma therapies.

Impact of asthma exacerbations and asthma triggers on asthma-related quality of life in patients with severe or difficult-to-treat asthma.

BACKGROUND: Few data are available that evaluate the relationship among asthma exacerbations, asthma triggers, and asthma-related quality of life (QoL). OBJECTIVE: To evaluate the impact of asthma exacerbations and asthma triggers on QoL. METHODS: Patients with severe or difficult-to-treat asthma, ages ≥ 13 years (n = 2679) from the TENOR (The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens) 3-year observational study were included. Exacerbations were defined hierarchically in descending order of severity (hospitalization, emergency department [ED] visit, steroid burst, no exacerbation) by using data from months 6 and 12. The total number (frequency) of exacerbations was assessed. Asthma-related QoL was measured at month 12 by using the Mini-Asthma QoL Questionnaire (Mini-AQLQ); self-reported asthma triggers were collected at baseline and annually. We used 1-way ANOVA to test for differences in Mini-AQLQ domain scores across asthma exacerbation severity, the total number of asthma exacerbations, and the number of asthma triggers. RESULTS: A significant decrease (P < .001) in Mini-AQLQ domain scores was seen with increasing severity of asthma exacerbation (no exacerbation, steroid burst, ED visit, and hospitalization); symptom (5.5, 4.8, 4.3, and 4.2), activity (5.8, 5.2, 4.6, and 4.4), emotional (5.6, 5.0, 4.4, and 4.2), exposure (5.0, 4.5, 4.0, and 3.9); and overall (5.5, 4.9, 4.3, and 4.1). Increasing exacerbation frequency and the number of baseline asthma triggers also were associated with significant decreases in Mini-AQLQ domain scores. An increasing number of asthma triggers were associated with an increase in severity and frequency of exacerbations. CONCLUSION: Avoidance of asthma triggers may reduce exacerbation rates and improve asthma-related QoL in patients with severe or difficult-to-treat asthma. Interventional studies are warranted to further explore these outcomes.

The reality of adherence to rhinitis treatment: identifying and overcoming the barriers.

Medical advances have allowed many patients with chronic diseases to lead relatively normal lives, but disparity between patient perceptions of "normal" and therapeutically defined disease control contributes to lowered adherence to treatment. This disconnect is greatest in diseases such as allergic rhinitis (AR) in which patients experience varying symptom severity over time-from asymptomatic periods to episodes of severe illness. This study was designed to evaluate the concept of adherence as applied to patients with AR. We reviewed the published literature. Adherence (or nonadherence) is an active process involving decision making on the part of the patient. Poor adherence with therapy can be the major barrier to achieving disease control, and the "on again, off again" approach to AR treatment embraced purposely by some patients may contribute to symptom lability, disease exacerbations, and higher costs. Evidence from surveys suggests that although specific educational interventions can temporarily improve adherence, in the long term most patients eventually revert to their former behavior. The available data suggest a need to reappraise how we address adherence with therapy in patients with chronic diseases with variable symptoms such as AR. The question is not just whether patient behavior can conform to recommended treatment plans, but whether it should. Experience suggests that successful strategies will be brief, easy to use, and capable of being tailored to individual patients in diverse clinical settings. Increased flexibility with medications is a corollary, particularly when patients are relatively asymptomatic (i.e., considered in control).

Exhaled nitric oxide as a tool in managing and monitoring difficult-to-treat asthma.

Most patients diagnosed with asthma maintain control reasonably well and do not experience asthma exacerbations; however, on average, 30% of patients achieve suboptimal control, have severe or difficult-to-treat asthma, and are relatively nonresponsive to the same medications that achieve and maintain asthma control for most patients. This small patient population of difficult-to-treat or severe asthma accounts for 80% of asthma medical costs. This study was designed to determine the potential U.S. payer cost savings resulting from an asthma specialist incorporating fractionated exhaled nitric oxide (FE(NO)) as an asthma management or monitoring tool to guide treatment of difficult-to-treat asthma patients. We present an annual medical resource use scenario typical of a difficult-to-treat asthma patient as well as five hypothetical scenarios of annual medical resource use for a difficult-to-treat asthma patient being managed with regular FE(NO) measurements in addition to current standard asthma management guidelines. We used the most conservative estimate of the potential asthma cost savings when FE(NO) measurement is used for difficult-to-treat asthma. The most likely clinical scenario assumes a 5% reduction in hospitalization and emergency department costs only. The inclusion of FE(NO) measurements to the asthma management strategy would essentially reach parity with the current standard of care, despite the additional cost of FE(NO) MEASUREMENTS: Additional scenarios were examined, all showed cost and use reduction across all medical resource usage categories. Use of exhaled NO measurement to guide asthma management, maintenance, and control in difficult-to-treat asthma would almost certainly result in cost savings to the payer.

Is there a role for aerosol nasal sprays in the treatment of allergic rhinitis: a white paper.

This White Paper presents the Consensus Statements derived from a Special Issues Board (SIB) held in Chicago, IL, in October 2010. The SIB was convened to address the question of whether there is a need for both aerosol and aqueous intranasal steroids (INSs) in the treatment of allergic rhinitis (AR). The faculty reviewed the published record of efficacy and safety of aerosol and aqueous INSs, as well as patient and physician satisfaction and preferences for currently available INSs, and burden of disease. Agreement on unmet needs also included the practice experience of the faculty and their colleagues. The body of evidence indicates that INSs are equally effective and well tolerated for most patients. However, differences exist among current aqueous formulations as well as between these products and their aerosol antecedents, based on the properties of the nasal spray. Aerosol formulations, although no longer available, may be preferred for some patients with specific pathophysiology and may be preferred by some patients based on sensory perception. There are good reasons to expand the currently available options of INSs by having both aerosol and aqueous formulations.

The economic burden associated with prior authorizations in an allergist office.

Costs for managed care organizations to process prior authorizations (PAs) for nonformulary medications have been estimated to be dollars 20-25 per request. Costs for physicians to process these requests have not been studied extensively. A data collection tool was developed and used by physicians and nurses to document time spent on processing PAs. Data were collected over 8 weeks and 117 requests were processed. Nurses averaged 5.6 +/- 6.5 calls per day per nurse and spent an average of 17 minutes per call. Physicians averaged 1.9 +/- 1.2 calls per day averaging 5.8 +/- 5.0 minutes per call. During the study period nurses spent >40 hours on 231 calls and physicians spent >8 hours on 154 calls. Based on the hourly rate of the nurses and physicians, the total cost in this specialty practice was dollars 17.77 per PA. Of the 117 PA requests, 98.7% were approved the first time they were processed. There are substantial costs with processing PAs for nonformulary drugs on the physician office side of managed care as well as on the insurance side of the process. Specialty physicians should have a different process for obtaining notformulary medications because almost 100% of their requests are granted.

What the asthma end points we know and love do and do not tell us.

Asthma is a disorder characterized by common features of reversible airflow obstruction and bronchial hyperreactivity in the setting of airway mucosal and submucosal inflammation. However, the clinical manifestations are syndromic and not unimodal. There is marked variability in severity of symptoms, natural history, risks of adverse outcomes, pathologic characteristics, and response to therapy. Understanding the relationship between these factors has been complicated by the variability of outcomes and the lack of correlation between them. There is a striking absence of correlation among the pathologic, physiologic, and clinical manifestations of the asthmatic disorders. Lung function tends to correlate poorly with clinical outcomes, and there is only modest correlation between clinical outcomes. Response to therapy is variable both externally (between patients) and internally, depending on which outcome is evaluated. A more complete understanding of the variability of disease and the genetic and environmental causes of the variability likely will change how we approach asthma and its therapy.

Symptom control and improved functioning: the effect of omalizumab on asthma-related quality of life (ARQL).

This investigation evaluated variability in asthma-related quality-of-life (ARQL) outcomes among patients randomized to omalizumab or placebo. Pooled data on the Asthma Quality of Life Questionnaire (AQLQ) from two trials were used (n = 948). Variability in ARQL outcomes was determined by categorizing AQLQ score changes according to minimal clinically important difference (MCID: 0.5 points) and large clinically important difference (LCID: 1.5 points) score changes. A greater proportion of patients achieved improvement in every domain of AQLQ scores during all periods with omalizumab compared with placebo. Omalizumab-treated patients showed greater clinically important improvement in ARQL compared with patients receiving placebo.

The utility of the Health Plan Employer Data and Information Set (HEDIS) asthma measure to predict asthma-related outcomes.

BACKGROUND: The Health Plan Employer Data and Information Set (HEDIS) measures are used extensively to measure quality of care. OBJECTIVE: To evaluate selected aspects of the HEDIS measure of appropriate use of asthma medications. METHODS: Claims data were analyzed for commercial health plan members who met HEDIS criteria for persistent asthma in 1999. The use of asthma medications was evaluated in the subsequent year with stratification by controller medication and a measure of adherence (days' supply). Multivariate logistic regressions were used to evaluate the association among long-term controller therapy for persistent asthma, adherence to therapy, and asthma-related hospitalizations or emergency department (ED) visits, controlling for demographic, preindex utilization, and other confounding characteristics. RESULTS: Of the 49,637 persistent asthma patients, approximately 35.7% were using 1 class of long-term controller medications, 18.4% were using more than 1 class, and 45.9% were not using such medication. More than 25% of the persistent asthma patients did not use any asthma medication in the subsequent year. Patients with low adherence to controller medication had a significantly higher risk (odds ratio [OR], 1.72; 95% confidence interval [CI], 1.42-2.08) of ED visit or hospitalization relative to patients not using any controllers compared with persons with moderate (OR, 0.84; 95% CI, 0.57-1.23) or high (OR, 0.70; 95% CI, 0.34-1.44) adherence. Patients receiving a high days' supply of inhaled corticosteroids had the lowest risk of ED visit or hospitalization (OR, 0.37; 95% CI, 0.05-2.69). CONCLUSIONS: Our findings suggest that refinements to the HEDIS measure method for identifying patients with persistent asthma may be needed.

Changing physician prescribing patterns through problem-based learning: an interactive, teleconference case-based education program and review of problem-based learning.

BACKGROUND: Although asthma guidelines have recommended the use of anti-inflammatory controller medications since 1991, studies have consistently shown widespread failure to follow the guidelines. Major barriers include lack of knowledge and the inability to operationalize knowledge. Improved continuing medical education methods should result in more effective learning by physicians and other health care professionals, leading to better adherence to guidelines, resulting in better outcomes. OBJECTIVE: To evaluate the effectiveness of an interactive, case-based, educational intervention, also known as problem-based learning, using a series of interactive, case-based teleconferences. METHODS: A series of interactive, case-based teleconferences was completed with 20 primary care physicians. Each case involved a child aged 16 months to 12 years with asthma. A 12-month analysis of physician prescribing patterns was conducted. RESULTS: Program acceptance by the 20 physicians was uniformly positive. Significant improvement was noted, with an overall increase in controller use. Review of prescription data showed an increase in inhaled corticosteroid use from an average of 2.54 to 7.76 refills per month for the 6 months after the intervention (P < .001). CONCLUSIONS: After participating in a unique educational intervention-problem-based learning using interactive, case-based teleconferences-the prescribing patterns of physicians were altered significantly toward better adherence to asthma guidelines, as demonstrated by an increased use of anti-inflammatory controller medications (inhaled corticosteroids and leukotriene antagonists).

Clinical and economic effects of suboptimally controlled asthma.

Patients with difficult-to-treat or suboptimally controlled asthma consume a disproportionate share of asthma health care resources. Treatment strategies that minimize exacerbations may decrease the need for unscheduled medical services, reduce emergency department visits, and minimize asthma-related hospitalizations. Clinical trial evidence indicates the immunoglobulin-E blocker omalizumab reduces the frequency of asthma exacerbations, minimizes symptoms, and improves lung function in patients with moderate-to-severe asthma that is inadequately controlled by inhaled corticosteroid therapy. Treatment with omalizumab of patients with suboptimally controlled asthma may reduce the clinical and economic burden of asthma.