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Address correspondence to: Beth Hahn, US Value Evidence & Outcomes, US Medical Affairs, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709-3398.
Retrospective study used claims data from patients with life-threatening asthma
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Mepolizumab led to marked reductions in exacerbations and oral corticosteroid use
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Mepolizumab is effective in patients with life-threatening asthma in the real world
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Pertinent to clinical practitioners managing patients with the most severe asthma
Abstract
Purpose
Patients with life-threatening asthma typically experience recurrent exacerbations, are dependent on oral corticosteroids (OCSs), and have considerable asthma-related health care costs. Data on the impact of mepolizumab on exacerbations and OCS use in patients with life-threatening asthma in real-world clinical practice are limited. This study assessed the impact of mepolizumab on exacerbation rates and OCS use in patients with life-threatening asthma in a real-word setting.
Methods
This retrospective study utilized data from US administrative claims from patients with life-threatening asthma. Eligible patients were treated between November 1, 2015, and December 31, 2017; were ≥12 years of age upon mepolizumab initiation (index date); and had undergone at least two mepolizumab administrations during the 6 months postindex. Data from the 12 months before (baseline) and after (follow-up) index were collected, with each patient serving as his or her own control. Life-threatening asthma was defined as at least three exacerbations and/or at least one asthma-related hospitalization during baseline, and/or a history of endotracheal intubation. Asthma exacerbation frequency and OCS use were assessed.
Findings
The analysis included 327 patients who received a mean (SD) of 10.6 (4.3) mepolizumab doses during follow-up. The percentage of patients experiencing at least one exacerbation and the mean exacerbation rate were significantly reduced from baseline to follow-up with mepolizumab, from 94.5% to 67.9% (P < 0.001), and from 3.2 to 1.5 events per patient per year, corresponding to a 53.1% relative reduction (P < 0.001). The percentage of patients with OCS claims was reduced by 12.6%, from 99.1% to 86.5% (P < 0.001). Of the patients who had a reduction in mean daily OCS use, most (57.9%, 140/242) had a reduction in mean daily OCS use of at least 50%.
Implications
These data from patients with life-threatening asthma in clinical practice demonstrated that asthma exacerbation and OCS use were significantly reduced with mepolizumab treatment.
It is defined as asthma that requires requires maximal, optimized inhaled corticosteroid (ICS) therapy plus another controller, to remain under control or as asthma that remains uncontrolled despite this therapy.
Global Initiative for Asthma (GINA). 2021 GINA Report, Global Strategy for Asthma Management and Prevention [GINA website]. Vol 2020 2020. Available at: https://ginasthma.org/gina-reports.
Patients with severe asthma have a high disease burden, with recurrent exacerbations, an increased risk for mortality, and increased hospitalization costs.
Comorbidity in severe asthma requiring systemic corticosteroid therapy: cross-sectional data from the Optimum Patient Care Research Database and the British Thoracic Difficult Asthma Registry.
Its use as an add-on therapy for patients with severe eosinophilic asthma, eosinophilic granulomatosis with polyangiitis, or hypereosinophilic syndrome has been approved.
The use of mepolizumab has been associated with reduced rates of exacerbation, exacerbation-related hospitalization, and oral corticosteroid (OCS) use in patients with severe eosinophilic asthma in placebo-controlled clinical trials.
Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial.
In patients with the most severe form, life-threatening asthma, reductions in exacerbation rate and daily OCS use were observed in the Phase IIIb open-label mepolizumab extension study COSMEX (A Phase 3a, Repeat Dose, Open-label, Long-term Safety Study of Mepolizumab in Asthmatic Subjects; ClinicalTrials.gov identifier: NCT02135692).
In that study, the definition of life-threatening asthma included a history of intubation, hospitalization for asthma exacerbation, and recurrent exacerbations (more than three within a 12-month period). The effectiveness of mepolizumab treatment in patients with asthma has also been mirrored in real-world settings.
Together, these study criteria indicate an unmet need for data on the effectiveness of mepolizumab in patients with life-threatening asthma in clinical practice.
Given the heavy disease burden in patients with life-threatening asthma,
the potential real-world impact of mepolizumab among these patients in clinical practice is clinically and economically relevant. The aim of this study was to augment the data on mepolizumab from the COSMOS clinical trial using an evaluation of the impact of the initiation of treatment with mepolizumab on the rates of exacerbation and exacerbation-related hospitalization, and on the use of OCS, in patients with life-threatening asthma in real-world clinical practice, using data from a database of US insurance claims.
Materials and Methods
Study Design
This study was a retrospective analysis (report no. 209656, HO-19-19603, GlaxoSmithKline, Research Triangle Park, North Carolina) of data from administrative claims in the IBM Watson Health MarketScan® commercial database (the same database used in a previous analysis of ours) was focused on assessing reductions in the use of OCSs in patients with severe asthma.
Patients with life-threatening asthma who were newly prescribed mepolizumab therapy from November 1, 2015, to December 31, 2017 were identified (Figure 1). The index date was defined as the date of the first medical or pharmacy claim for mepolizumab administration. Data from each patient during the 12 months prior to and including the index date (baseline) and during the 12 months following the index date (follow-up) were examined. The study protocol was exempt from institutional review board approval owing to the preexisting and deidentified nature of the claims data.
Figure 1Patient disposition. Data were categorized according the criteria for life-threatening asthma (gray); patients may be included in multiple categories. Baseline was defined as the 12 months before and including the index date (day of first administration of mepolizumab); follow-up was defined as the 12 months after the index date. ICD = International Classification of Diseases; OCS = oral corticosteroid.
Eligible patients were ≥12 years of age, continuously enrolled in a medical and pharmacy benefits program during baseline and follow-up, had physician-diagnosed asthma during baseline, and received at least two administrations of mepolizumab during the first 6 months of follow-up. Data from patients who received mepolizumab once and those in whom mepolizumab was not well tolerated were excluded. Patients were also excluded from the study if they had evidence of mepolizumab use during baseline, or evidence of omalizumab, reslizumab, benralizumab, or dupilumab use during baseline and follow-up (see Supplemental Table I in the online version at.
Life-threatening asthma was defined according to the criteria used in the COSMEX clinical trial (see the Appendix),
but modified to fit claims data. In this study, patients were required to meet at least one of the following criteria: at least three asthma exacerbations and/or at least one asthma-related hospitalization (with asthma as the primary diagnosis) during baseline; evidence of endotracheal intubation using all available claims history prior to index (see Supplemental Table I); and/or a prescription for OCS with a mean daily dose of ≥10 mg prednisone equivalents within the last 90 days of baseline.
End Points and Assessments
The primary end points were the rate of all asthma exacerbations (expressed as events per patient per year [PPPY]), and the rate of exacerbations requiring hospitalization during baseline and follow-up. The definition of exacerbation was based on that in the COSMEX study
: at least one outpatient or emergency department claim with a diagnosis of asthma (defined as International Classification of Diseases [ICD]-9 code 493.xx, ICD-10 code J45.xx) in addition to at least one claim for an SCS (IM, IV, or PO) within –4/+5 days of the encounter. Exacerbations resulting in hospitalization were defined as inpatient hospital admissions with a primary diagnosis of asthma. The exacerbation period started on the date of the claim or inpatient admission and ended 13 days later or on the inpatient admission discharge date. Exacerbations occurring within 14 days following the end of a prior exacerbation were classed as one episode. Data from claims of scheduled administrations of mepolizumab (see Supplemental Table II) were excluded from the analysis of exacerbation, consistent with previous studies.
The percentage of patients with at least one exacerbation, in addition to the mean rate of exacerbations, expressed as the mean number of exacerbations PPPY, was calculated.
The secondary end point was the use of a maintenance OCS during baseline and follow-up, based on national drug codes and health care common procedure coding systems. The percentage of patients with at least one claim for an OCS, the mean number of claims for an OCS per patient, percentage reduction in mean daily OCS use, the percentage of patients with OCS bursts, and the mean number of OCS bursts were also evaluated. Mean daily OCS use was calculated as the sum of OCS doses across all pharmacy claims for OCSs, divided by 365 days. OCS burst was defined as a mean daily dose of ≥20 mg for 3 to 28 days and one outpatient or emergency department claim with a diagnosis of asthma in any position ±7 days of the date of the pharmacy claim. Long-term OCS use was defined as a mean daily OCS dose of ≥5 mg through baseline and follow-up. OCS use was assessed using prednisone equivalents.
Statistical Analysis
The demographic characteristics of the patients on the index date were analyzed, and the clinical characteristics during baseline are described. The mean (SD) values for continuous variables are reported, and counts and percentages for nominal or categorical variables are reported. McNemar's tests were used for differences in nominal and categorical variables; paired t-tests were used for differences in interval and continuous variables. A P value of 0.05 was the maximum P value considered statistically significant.
Results
Patient Population
In total, 327 patients met the study inclusion criteria, and their data were included in the analysis (Figure 1). The mean (SD) age was 49.6 (11.3) years, with 40.0% (n = 132) of patients aged 55 to 64 years. Most patients (210 patients [64.0%]) were female (Table 1). The mean (SD) Deyo–Comorbidity Index (scale, 1–6) was 1.5 (1.0), with the two most common acute comorbidities being allergic rhinitis (226 [69.1%]) and respiratory infections (185 [56.6%]), and the two most common chronic comorbidities being gastroesophageal reflux disease (124 [37.9%]) and chronic obstructive pulmonary disease (COPD; 121 [37.0%]) (Figure 2). During the last 90 days of the baseline period, 51.1% of patients (n = 167) were receiving a high-dose ICS or ICS/long-acting β2-agonists (see Supplemental Table III).
Table 1Demographic characteristics of the patients at index
Figure 2Selected comorbidities during baseline, defined as the 12 months before and including the index date (day of first administration of mepolizumab). Respiratory infection was defined as an upper respiratory tract infection of any cause. None of the patients presented with malignant neoplasm of respiratory or intrathoracic organs.
The mean (SD) number of mepolizumab administrations during follow-up was 10.6 (4.3); 66.1% of patients (n = 216) had ≥10 mepolizumab administrations. Compared with baseline, the use of most asthma medications was reduced during follow-up, with statistical significance reached with a short-acting β2-agonist alone or in combination with a short-acting muscarinic antagonist (P < 0.001), a short-acting muscarinic antagonist alone (P < 0.001), an ICS alone or in conjunction with a long-acting β2-agonist (P = 0.039), and leukotriene use (P < 0.001) (see Supplemental Figure 1).
Asthma Exacerbations
The mean (SD) rate of exacerbations was significantly reduced, from 3.2 (1.5) to 1.5 (1.5) events PPPY from baseline to follow-up (P < 0.001), corresponding to a relative reduction of 53.1% (Figure 3A). The relative reduction in the rate of exacerbations requiring hospitalization (50.0%; P < 0.001) was similar to that of total exacerbations (Figure 3A).
Figure 3Mean (SD) number (A) and prevalence (B) of asthma exacerbations and hospitalizations during baseline and follow-up. Baseline was defined as the 12 months before and including the index date (day of first administration of mepolizumab); follow-up was defined as the 12 months after the index date. Exacerbation that occurred on the index date was considered a baseline exacerbation.
During baseline, 94.5% of patients experienced at least one exacerbation, which was reduced to 67.9% during follow-up (P < 0.001) (Figure 3B). The percentage of patients with an exacerbation requiring hospitalization was also reduced, from 15.9% to 5.2% from baseline to follow-up (P < 0.001) (Figure 3B).
Use of Maintenance OCS
During baseline, 99.1% of patients (n = 324) had at least one claim for an OCS, which was decreased to 86.5% (283) during follow-up (P < 0.001) (Figure 4A). Of the patients who had a reduction in mean daily OCS use (74.0%, 242), the majority (57.9%, 140/242) had a relative reduction of ≥50% (Figure 4B).
Figure 4A, Prevalence of oral corticosteroid (OCS) use during baseline and follow-up. B, Percentage reductions in mean daily OCS dose in patients with a reduction in OCS use during follow-up compared with during baseline. C, Mean (SD) OCS claims and bursts per year during baseline and follow-up. Baseline was defined as the 12 months before and including the index date (first day of administration of mepolizumab); follow-up was defined as the 12 months after the index date; long-term OCS use was defined as a mean dose of ≥5 mg over baseline and follow-up; OCS burst was defined as a mean daily dose of ≥20 mg prednisone equivalents for a duration of 3 to 28 days in addition to a claim for either an outpatient or emergency department visit with a diagnosis of asthma (International Classification of Diseases [ICD]-9: 493.xx, ICD-10: J45.xx) ± 7 days of the pharmacy claim. *Three of 327(0.9%) patients did not use an OCS during baseline.
During baseline, 63.0% of patients (n = 206) were receiving long-term treatment with an OCS. During follow-up, the percentage of patients with long-term OCS use was decreased to 42.8% (140) (P < 0.001) (Figure 4A). In agreement with this, the mean number of OCS claims PPPY was reduced by 31.6% (P < 0.001) (Figure 4C). The percentage of patients with an OCS burst during baseline was 81.3% (266), with a mean (SD) number of OCS bursts PPPY of 2.7 (2.3) (Figure 4C). During follow-up, the percentage of patients with an OCS burst was decreased to 59.0% (P < 0.001). Likewise, the mean number of OCS bursts PPPY was also reduced, by 44.4%, during follow-up (P < 0.001) (Figure 4C).
Discussion
To the best of our knowledge, this study is the first to demonstrate the impact of mepolizumab on exacerbation-related burden in patients with life-threatening asthma in real world clinical practice. Mepolizumab treatment was associated with both a reduced rate, and a reduced percentage of patients experiencing, exacerbations, in addition to reduced OCS claims, compared with baseline. These findings are important to patients with life-threatening asthma, health care professionals, and payors, as these patients experience the greatest disease burden, have high asthma-related health care costs, and have the greatest unmet need.
As with any claims database, the MarketScan® Research Database relies on administrative claims data for clinical detail, and these data were subject to coding limitations and entry error.
Given that medications administered during inpatient admission were not captured by the database, the total number of patients who received asthma treatments was likely to have been underestimated. Furthermore, the definition of life-threatening asthma included the use of an OCS; however, the reason for OCS use was not possible to determine from the available records. Nonetheless, the majority of patients (50/68) exclusively meeting the OCS-related definition of life-threatening asthma had experienced at least one asthma exacerbation during baseline, and given that these patients were receiving an OCS shortly before the initiation of mepolizumab (within 90 days), it was likely that OCS use was linked to asthma. Likewise, OCS bursts and asthma exacerbation-related outpatient claims included patients with a diagnosis of asthma in any position, and as such these analyses may have included patients with asthma as a nonprimary diagnosis, such as those diagnosed with EGPA; however, the percentage within the study was small (4%). Additional limitations included that only patients with private insurance claims in the United States were included in the analysis, most patients treated with mepolizumab included in this study were employed, and patients who died in the 12 months following mepolizumab administration were not included in the study population, which collectively suggest that this patient population may not have been representative of the general population of patients with life-threatening asthma. The self-paired pre-and-post approach used in this study compared each patient's end points between their own baseline and follow-up. While this method accounts for time-fixed confounding factors, it does not account for time-varying confounding factors, such as changes in medication use or clinical and behavioral traits (eg, exercise, smoking, and alcohol consumption), and is therefore at risk for bias from temporal trends in the end points,
Furthermore, quality-of-life measures and smoking status and history are difficult to capture in retrospective analyses of data from claims databases, as information is reported for billing purposes. Nonetheless, temporal trends are of greater concern in studies with durations longer than 2 years. Moreover, in the present study it was assumed that the changes in exacerbation rates observed during follow-up were the result of mepolizumab treatment, rather than an improvement resulting from any trial effect, an assumption consistent with a previous study.
Notably, over one third of the patients with life-threatening asthma in the study had comorbid COPD, defined as at least one claim with an ICD-9/ICD-10 diagnosis code for COPD. However, characteristic symptoms of COPD, such as fixed airflow obstruction, may overlap with asthma symptoms, wherein the absence of smoking-related fixed airflow obstruction could reflect airway remodeling.
Global Initiative For Asthma. Global Strategy for Asthma Management and Prevention. Vol 20212021, https://ginasthma.org/gina-reports/. 26 November, 2021.
However, the findings from one study suggested that concurrent asthma and COPD may be overestimated due to these overlapping symptoms, particularly when relying on health care records,
although it was beyond the scope of this study to fully validate the accuracy of any COPD diagnosis. The findings are in line with those from a meta-analysis of data from 27 studies in which the estimated prevalence of asthma–COPD overlap among patients with asthma was 3.2% to 51.4%, depending on the diagnostic criteria used.
Importantly, we did not perform sensitivity analyses to account for the presence of comorbid COPD or any other comorbidities; however, the presence of such comorbidities was likely to have been reflective of a real-world population with life-threatening asthma.
In this study, the rate of exacerbations, including those requiring hospitalization, was reduced by >50% after the initiation of mepolizumab treatment. These real-world findings extend data from clinical trials in patients with severe eosinophilic asthma.
For example, in the open-label, long-term extension COSMEX study, which evaluated end points in patients in whom clinical benefit with mepolizumab had been shown in previous lead-in randomized controlled trials,
the exacerbation rate was reduced to 1 event/y compared with 5 events/y in the 12 months before enrollment in the initial lead-in trial; this reduction was sustained throughout the 172-week COSMEX extension study.
Furthermore, the present data are consistent with findings from other studies in patients with asthma or severe eosinophilic asthma in clinical practice, in which reductions in the rates of exacerbations were observed with mepolizumab initiation, compared with a pre–mepolizumab treatment period.
Collectively, these findings suggest that mepolizumab is of clinical benefit in patients with life-threatening asthma who are treated in real world clinical practice.
This is important because asthma disease severity, as indicated by high-intensity asthma treatment, has been linked to an increased risk for further exacerbations,
and severe and frequent exacerbations have been associated with an irreversible decline in lung function, resulting in long-term adverse structural and functional changes in the airways.
Moreover, recent hospitalizations or emergency department visits for the treatment of asthma have been associated with an increased risk for asthma-related mortality.
Therefore, a reduction in the exacerbation rate in these patients may not only lower the acute exacerbation–related burden, the risk for death, and the irreversible decline in lung function resulting from asthma, but also may ameliorate the overall long-term health care burden associated with life-threatening asthma.
We also observed significant reductions from baseline in the percentages of both patients with burst and long-term OCS use. Of those in whom mean daily OCS use was reduced, most patients experienced a 50% or greater reduction. These data support and extend results from clinical trials and real-world study results in severe and/or eosinophilic asthma.
Global Initiative For Asthma. Global Strategy for Asthma Management and Prevention. Vol 20212021, https://ginasthma.org/gina-reports/. 26 November, 2021.
Comorbidity in severe asthma requiring systemic corticosteroid therapy: cross-sectional data from the Optimum Patient Care Research Database and the British Thoracic Difficult Asthma Registry.
Comorbidity in severe asthma requiring systemic corticosteroid therapy: cross-sectional data from the Optimum Patient Care Research Database and the British Thoracic Difficult Asthma Registry.
Therefore, any reduction in OCS use is clinically significant in these patients, given that it may mitigate the disease burden resulting from OCS-associated adverse events, and that it may reduce the associated strain on health care resources. The results from the present study provide further evidence of the OCS-sparing effect of mepolizumab that has been demonstrated in formal clinical trials and previous studies in clinical practice.
In these patients with a history of life-threatening asthma in read world clinical practice, asthma exacerbations and OCS use were significantly reduced with mepolizumab treatment compared with baseline. These findings are of particular and unique interest to clinical practitioners who manage patients with the most severe disease (ie, life-threatening asthma).
Acknowledgment
Medical writing support was provided by Roisin McCorkell, MSc, Fishawack Indicia Ltd (UK), part of Fishawack Health, and was funded by GlaxoSmithKline.
Author Contributions
J.S., M.B., E.R.P., D.M., J.W., and B.H. were involved in the conception or design of the study. E.R.P. and B.H. were involved in the acquisition of data, and J.S., N.M., M.B., E.P., D.M., J.W., and B.H. contributed to the analysis or interpretation of data. J.S., N.M., M.B., E.R.P., D.M., J.W., and B.H. drafted the work or revised it critically for important intellectual content, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work.
Disclosure
This study was funded by GlaxoSmithKline (report no. 209656, HO-19-19603). GlaxoSmithKline supported the study design, data collection, analysis, manuscript preparation, and data interpretation for the manuscript. All of the authors approved the manuscript for submission.
J.S., M.B., and B.H. are employees of GlaxoSmithKline and hold stocks/shares in GlaxoSmithKline. J.S. is a former employee of Partners Healthcare/Brigham and Women's Hospital/Harvard Medical School. N.M. is a former employee of GlaxoSmithKline and is employed by, and holds stocks/shares in, Amgen. E.R.P., D.M., and J.W. are employees of IBM Watson Health, which received funds from GlaxoSmithKline for this study. The authors have indicated that they have no other conflicts of interest with regard to the content of this article.
Global Initiative for Asthma (GINA). 2021 GINA Report, Global Strategy for Asthma Management and Prevention [GINA website]. Vol 2020 2020. Available at: https://ginasthma.org/gina-reports.
Comorbidity in severe asthma requiring systemic corticosteroid therapy: cross-sectional data from the Optimum Patient Care Research Database and the British Thoracic Difficult Asthma Registry.
Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial.
Global Initiative For Asthma. Global Strategy for Asthma Management and Prevention. Vol 20212021, https://ginasthma.org/gina-reports/. 26 November, 2021.
Index was defined as the day of first administration of mepolizumab in the study period.
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