- Email: [email protected]
Omalizumab (Xolair) May Normalize IgE Production Rate In Patients With Moderate-To-Severe Atopic Asthma
S152 Abstracts
580
SUNDAY
Identification of a Threshold for High Utilization of Short Acting Beta2 Agonists in a Commercially Insured Adult Asthmatic Population in the United States C. M. Blanchette1,2, H. Silver1, H. Petersen1, S. Kamble3, D. Meddis4, B. Gutierrez4; 1Lovelace Respiratory Research Institute, Albuquerque, NM, 2 University of North Carolina School of Pharmacy, Chapel Hill, NC, 3University of North Carolina, Charlotte, NC, 4AstraZeneca, Wilmington, DE. RATIONALE: High levels of short-acting beta2 agonists (SABA) are associated with asthma exacerbations. We explored SABA utilization patterns in adult asthmatics to estimate a threshold associated with asthma exacerbations. METHODS: A retrospective cohort study was conducted with adults (aged 18-56 years; n 5 59,653) with asthma, two-year continuous enrollment in the PHARMetrics database between 7/2003- 6/2007, 1 hospitalization/emergency department (ED) or 2 outpatient claims with an ICD-9 code 493.XX and 1 asthma medication claim in each of the two years of observation. Adults with COPD and diseases associated with chronic oral steroid use were excluded. Second year SABA utilization was converted to canister-count/year and categorized into 1): 0, ½-2, 2½-6, 6½-12, and >12; and 2) 0-5 and 6. Logistic regression was used to estimate the risk of asthma exacerbation, defined as an oral steroid claim, asthma-related hospitalization or ED visit. Covariates included age, sex, region, postindex asthma controller use, several first year severity measures and comorbidities. RESULTS: Utilization of SABA canisters/year included 28.0% with 0, 37.8% with ½-2, 20.6% with 2½-6, 9.2% with 6½-12, 4.4% with >12 and 16.9% with 6 (83.1% 0-5). Compared to 0 canisters/year, higher SABA utilization and high exacerbation risk were observed [½-2 (OR: 1.28; CI: 1.18-1.38), 2½-6(OR: 1.57; CI: 1.44-1.71), 6½-12(OR: 1.86; CI: 1.67-2.07), and >12(OR: 1.95; CI: 1.70-2.23)] Patients with 6 canisters/year had a 45% greater exacerbation risk (OR: 1.45; CI: 1.35-1.56) compared to 0-5. CONCLUSIONS: Increased use of SABA signaled increased exacerbation risk. A threshold beyond 6 SABA canisters/year suggests a need for re-examining asthma treatment in Adults.
581
The Impact of Geographic Variation on Racial Disparities in Asthma: Controller Medication Use among Medicaid Asthmatics in Four Large States P. L. Yong1,2, R. M. Werner1,2; 1University of Pennsylvania School of Medicine, Philadelphia, PA, 2Philadelphia Veterans Affairs Medical Center, Philadelphia, PA. RATIONALE: Significant literature documents racial disparities in quality of care provided to asthmatics. One explanation for these disparities is differences in healthcare practices and resources across geography - that is, disparities exist because of differences in quality between providers of different regions rather than patients being treated differently by providers within the same region. We tested the role of geography in explaining disparities in asthma care. METHODS: We performed a retrospective cohort analysis of persistent asthmatics continuously enrolled in Medicaid in California, Florida, New York and Ohio from 2001 - 2002 and calculated each patient’s care quality using the HEDIS appropriate medications metric. With multivariate regression, controlling for age and sex, we examined whether geography might explain existing racial disparities in care by estimating disparities in the HEDIS metric with and without county and zip-code fixed effects. If adding geographic fixed effects decreased disparities, it suggests that disparities are predominantly due to variation in geography. RESULTS: We identified 95,830 white (64.8%) and black (35.2%) asthmatics. Adjusting for age and sex, blacks obtained controller medication less frequently than whites (81.3% vs. 82.3% [P < 0.001]). Disparities decreased after including county and zip-code fixed effects, with the difference in rate of controller medication use decreasing to 0.558 (P 5 0.066) and 0.016 percentage points (P 5 0.965), respectively. CONCLUSIONS: Racial disparities in asthma care significantly decreased after adjusting for geographic area of residence, suggesting that
J ALLERGY CLIN IMMUNOL FEBRUARY 2009
disparities exist between rather than within geographic regions. Efforts to eliminate racial disparities in quality of care for asthmatics should consider where patients are seeking their care.
582
The Minimally Important Difference (MID) of the Asthma Control Test (ACT) Administered by Telephone M. Schatz1, M. Kosinski2, A. Yarlas2, J. Hanlon2, P. Jhingran3; 1Kaiser Permanente, San Diego, CA, 2QualityMetric, Lincoln, RI, 3GlaxoSmithKline, Research Triangle Park, NC. RATIONALE: The ACT has been well validated, but an MID has not been established. METHODS: The ACTwas administered during automated phone calls using speech recognition technology to Kaiser Permanente members aged 18-56. Distributional methods for determining the MID included 0.5 standard deviation (SD), 1 standard error of measurement (SEM), and 2 SEM, the latter particularly important in assessing meaningful intra-individual change. SEM was calculated as SD*SQRT (1-Cronbach’s alpha). Anchor-based methods assessed the relationship of differences in ACT scores to the risk over the next 12 months of excess beta agonist dispensings (> 6 canisters per year) or exacerbations (asthma hospitalization, ED visit, or oral corticosteroid dispensing) from administrative data. RESULTS: In the 2244 patients who completed ACT scores, the mean (sd) ACT score was 19.5 (4.3). 0.5 SD was 2.10, 1 SEM was 2.05, and 2 SEM was 4.10. ACT score as a continuous variable was linearly related to the subsequent risk of excess beta agonist use and exacerbations (p < 0.001). A difference of 2 points on ACT was associated with a subsequent 46% increased risk (95% CI 43-49%) of excess beta agonist use and a 21% increased risk (95% CI 19-23%) of exacerbations. CONCLUSIONS: The data support an MID for the ACT administered by telephone of 2 points. An MID of 4 points for intra-individual changes reduces the likelihood that the change is due to measurement error. Whether these results can be extrapolated to the ACT administered by other modes of administration requires further study.
583
Omalizumab (Xolair) May Normalize IgE Production Rate In Patients With Moderate-To-Severe Atopic Asthma P. Lowe1, S. Tannenbaum2, A. Gautier1, M. Massanari2, Z. Panahloo3; 1 Novartis Pharma AG, Basel, Switzerland, 2Novartis Pharmaceuticals Corporation, East Hanover, NJ, 3Novartis Horsham Research Centre, Horsham, United Kingdom. RATIONALE: Long-term anti-IgE therapy may attenuate the excess IgE expression observed in atopic individuals. METHODS: We investigated and quantified the timescale over which IgE production could be normalized using a direct-binding model incorporating both dissociation constants and kinetic parameters for omalizumab, IgE and omalizumab-IgE complexes. This was written into a nonlinear mixed effect PK/PD model accounting for inter- and intra-patient variability. Input data were total serum omalizumab (sum of free and complex), free and total IgE from 1682 individuals with allergic asthma or rhinitis in four clinical studies of omalizumab. Two versions of the model were fitted: one with constant parameters; the other where IgE production rate could change over time. Normal IgE production was defined as 264 mg/day. RESULTS: Each model allowed relatively precise parameter estimation (maximum residual error, 25% coefficient of variation [CV]). The timechanging IgE production model gave a highly significant 2067-point decrease in log-likelihood objective function versus the constant IgE expression version. The estimated mean initial IgE production rate was 1840 mg/ day (inter-patient CV, 29%). In control patients, IgE production appears to increase slowly at an average rate of 3.6% per year. IgE production rate decreased in omalizumab-treated patients and was projected to stabilize, ultimately, at 132 mg/day (168% CV). The apparent half-life of this change was 1.6 years (80% CV) providing a testable hypothesis that atopic patients may achieve normal IgE expression after 3-4 half-lives. CONCLUSIONS: PK/PD models based on total and free IgE data suggest that, over the long term, omalizumab reduces IgE production towards normal (non-atopic) rates.
580
SUNDAY
Identification of a Threshold for High Utilization of Short Acting Beta2 Agonists in a Commercially Insured Adult Asthmatic Population in the United States C. M. Blanchette1,2, H. Silver1, H. Petersen1, S. Kamble3, D. Meddis4, B. Gutierrez4; 1Lovelace Respiratory Research Institute, Albuquerque, NM, 2 University of North Carolina School of Pharmacy, Chapel Hill, NC, 3University of North Carolina, Charlotte, NC, 4AstraZeneca, Wilmington, DE. RATIONALE: High levels of short-acting beta2 agonists (SABA) are associated with asthma exacerbations. We explored SABA utilization patterns in adult asthmatics to estimate a threshold associated with asthma exacerbations. METHODS: A retrospective cohort study was conducted with adults (aged 18-56 years; n 5 59,653) with asthma, two-year continuous enrollment in the PHARMetrics database between 7/2003- 6/2007, 1 hospitalization/emergency department (ED) or 2 outpatient claims with an ICD-9 code 493.XX and 1 asthma medication claim in each of the two years of observation. Adults with COPD and diseases associated with chronic oral steroid use were excluded. Second year SABA utilization was converted to canister-count/year and categorized into 1): 0, ½-2, 2½-6, 6½-12, and >12; and 2) 0-5 and 6. Logistic regression was used to estimate the risk of asthma exacerbation, defined as an oral steroid claim, asthma-related hospitalization or ED visit. Covariates included age, sex, region, postindex asthma controller use, several first year severity measures and comorbidities. RESULTS: Utilization of SABA canisters/year included 28.0% with 0, 37.8% with ½-2, 20.6% with 2½-6, 9.2% with 6½-12, 4.4% with >12 and 16.9% with 6 (83.1% 0-5). Compared to 0 canisters/year, higher SABA utilization and high exacerbation risk were observed [½-2 (OR: 1.28; CI: 1.18-1.38), 2½-6(OR: 1.57; CI: 1.44-1.71), 6½-12(OR: 1.86; CI: 1.67-2.07), and >12(OR: 1.95; CI: 1.70-2.23)] Patients with 6 canisters/year had a 45% greater exacerbation risk (OR: 1.45; CI: 1.35-1.56) compared to 0-5. CONCLUSIONS: Increased use of SABA signaled increased exacerbation risk. A threshold beyond 6 SABA canisters/year suggests a need for re-examining asthma treatment in Adults.
581
The Impact of Geographic Variation on Racial Disparities in Asthma: Controller Medication Use among Medicaid Asthmatics in Four Large States P. L. Yong1,2, R. M. Werner1,2; 1University of Pennsylvania School of Medicine, Philadelphia, PA, 2Philadelphia Veterans Affairs Medical Center, Philadelphia, PA. RATIONALE: Significant literature documents racial disparities in quality of care provided to asthmatics. One explanation for these disparities is differences in healthcare practices and resources across geography - that is, disparities exist because of differences in quality between providers of different regions rather than patients being treated differently by providers within the same region. We tested the role of geography in explaining disparities in asthma care. METHODS: We performed a retrospective cohort analysis of persistent asthmatics continuously enrolled in Medicaid in California, Florida, New York and Ohio from 2001 - 2002 and calculated each patient’s care quality using the HEDIS appropriate medications metric. With multivariate regression, controlling for age and sex, we examined whether geography might explain existing racial disparities in care by estimating disparities in the HEDIS metric with and without county and zip-code fixed effects. If adding geographic fixed effects decreased disparities, it suggests that disparities are predominantly due to variation in geography. RESULTS: We identified 95,830 white (64.8%) and black (35.2%) asthmatics. Adjusting for age and sex, blacks obtained controller medication less frequently than whites (81.3% vs. 82.3% [P < 0.001]). Disparities decreased after including county and zip-code fixed effects, with the difference in rate of controller medication use decreasing to 0.558 (P 5 0.066) and 0.016 percentage points (P 5 0.965), respectively. CONCLUSIONS: Racial disparities in asthma care significantly decreased after adjusting for geographic area of residence, suggesting that
J ALLERGY CLIN IMMUNOL FEBRUARY 2009
disparities exist between rather than within geographic regions. Efforts to eliminate racial disparities in quality of care for asthmatics should consider where patients are seeking their care.
582
The Minimally Important Difference (MID) of the Asthma Control Test (ACT) Administered by Telephone M. Schatz1, M. Kosinski2, A. Yarlas2, J. Hanlon2, P. Jhingran3; 1Kaiser Permanente, San Diego, CA, 2QualityMetric, Lincoln, RI, 3GlaxoSmithKline, Research Triangle Park, NC. RATIONALE: The ACT has been well validated, but an MID has not been established. METHODS: The ACTwas administered during automated phone calls using speech recognition technology to Kaiser Permanente members aged 18-56. Distributional methods for determining the MID included 0.5 standard deviation (SD), 1 standard error of measurement (SEM), and 2 SEM, the latter particularly important in assessing meaningful intra-individual change. SEM was calculated as SD*SQRT (1-Cronbach’s alpha). Anchor-based methods assessed the relationship of differences in ACT scores to the risk over the next 12 months of excess beta agonist dispensings (> 6 canisters per year) or exacerbations (asthma hospitalization, ED visit, or oral corticosteroid dispensing) from administrative data. RESULTS: In the 2244 patients who completed ACT scores, the mean (sd) ACT score was 19.5 (4.3). 0.5 SD was 2.10, 1 SEM was 2.05, and 2 SEM was 4.10. ACT score as a continuous variable was linearly related to the subsequent risk of excess beta agonist use and exacerbations (p < 0.001). A difference of 2 points on ACT was associated with a subsequent 46% increased risk (95% CI 43-49%) of excess beta agonist use and a 21% increased risk (95% CI 19-23%) of exacerbations. CONCLUSIONS: The data support an MID for the ACT administered by telephone of 2 points. An MID of 4 points for intra-individual changes reduces the likelihood that the change is due to measurement error. Whether these results can be extrapolated to the ACT administered by other modes of administration requires further study.
583
Omalizumab (Xolair) May Normalize IgE Production Rate In Patients With Moderate-To-Severe Atopic Asthma P. Lowe1, S. Tannenbaum2, A. Gautier1, M. Massanari2, Z. Panahloo3; 1 Novartis Pharma AG, Basel, Switzerland, 2Novartis Pharmaceuticals Corporation, East Hanover, NJ, 3Novartis Horsham Research Centre, Horsham, United Kingdom. RATIONALE: Long-term anti-IgE therapy may attenuate the excess IgE expression observed in atopic individuals. METHODS: We investigated and quantified the timescale over which IgE production could be normalized using a direct-binding model incorporating both dissociation constants and kinetic parameters for omalizumab, IgE and omalizumab-IgE complexes. This was written into a nonlinear mixed effect PK/PD model accounting for inter- and intra-patient variability. Input data were total serum omalizumab (sum of free and complex), free and total IgE from 1682 individuals with allergic asthma or rhinitis in four clinical studies of omalizumab. Two versions of the model were fitted: one with constant parameters; the other where IgE production rate could change over time. Normal IgE production was defined as 264 mg/day. RESULTS: Each model allowed relatively precise parameter estimation (maximum residual error, 25% coefficient of variation [CV]). The timechanging IgE production model gave a highly significant 2067-point decrease in log-likelihood objective function versus the constant IgE expression version. The estimated mean initial IgE production rate was 1840 mg/ day (inter-patient CV, 29%). In control patients, IgE production appears to increase slowly at an average rate of 3.6% per year. IgE production rate decreased in omalizumab-treated patients and was projected to stabilize, ultimately, at 132 mg/day (168% CV). The apparent half-life of this change was 1.6 years (80% CV) providing a testable hypothesis that atopic patients may achieve normal IgE expression after 3-4 half-lives. CONCLUSIONS: PK/PD models based on total and free IgE data suggest that, over the long term, omalizumab reduces IgE production towards normal (non-atopic) rates.