Abstract
Background: Information is limited regarding the cost of pulmonary exacerbations (PEx) among patients with cystic fibrosis in the United States.
Methods: To examine PEx costs, medical chart data were linked to insurance claims for patients aged ≥6 years who had commercial coverage from a large US health insurer affiliated with Optum during 2008–2013. A PEx was categorized as an episode requiring newly started (1) oral antibiotics (PEx-O) or (2) intravenous (IV) antibiotics and/or inpatient stay (PEx-IV).
Results: Among 241 patients, 88.0% had ≥1 PEx (2.9/year) of any type, and 48.1% had ≥1 PEx-IV. Prior PEx-IV was the strongest risk factor for subsequent PEx-IV. The mean cost per episode was $12,784 for PEx of any type and $36,319 for PEx-IV. Patients with worse lung function were more likely to experience a PEx and incurred higher annual PEx-related costs.
Limitations: This was an observational study using a convenience sample of patients with commercial coverage from a large US health insurer whose medical charts were available for abstraction. Results of the study may not be generalizable to individuals with Medicaid coverage and other types of insurance, or to the uninsured.
Conclusions: Most patients experience ≥1 PEx annually, and nearly half require IV antibiotics and/or inpatient stay at considerable cost.
Introduction
Pulmonary exacerbations (PEx) are associated with reduced health-related quality of lifeCitation1 and higher mortality riskCitation2 in patients with cystic fibrosis (CF). Exacerbations also accelerate the trajectory of lung function declineCitation3,Citation4 and have been closely linked to future exacerbation riskCitation5.
Despite their clinical significance, there is no standardized definition of PExCitation6. In the United States, diagnostic criteria and treatment strategies vary widely among individual clinicians and between and within CF centers of careCitation7. While PEx are commonly defined in research studies as acute episodes requiring intravenous (IV) antibiotic treatment, in clinical practice, exacerbations are also commonly treated with oral antibiotic therapyCitation8. Further, patterns of use have changed in different directions for children and adults over time, with non-IV treatment incidence increasing among children and declining among teenagers and adultsCitation9.
Given the clinical significance of PEx and the evolving approach to their management, an understanding of the burden they impose is needed. Although previous studies have found that CF patients incur substantial overall healthcare costsCitation10–13, data on costs attributable specifically to PEx are lacking. The goal of this study was to examine the burden of PEx and associated costs among a national sample of pediatric and adult patients with CF with commercial coverage from a large US health insurer affiliated with Optum from 2008 to 2013. Clinical information from medical charts was linked with a national health claims database to assess the frequency of PEx, PEx-related healthcare costs, and risk factors for PEx. A portion of the results of this study was presented at the 38th European Cystic Fibrosis Conference, 10–13 June 2015, Brussels, BelgiumCitation14,Citation15.
Methods
Study design and data source
In this retrospective study, medical chart data were combined with administrative claims data from a large, US health insurer with national coverage. The health plan database included medical claims (with diagnostic and procedure codes) and pharmacy claims. Data from medical charts were abstracted to collect patient characteristics and clinical outcomes not available in the claims database. The participating providers were located throughout the four US geographic regions (Northeast, Midwest, South, West).
The study was conducted in accordance with US Health Insurance Portability and Accountability Act (HIPAA) guidelines. An institutional review board and affiliated privacy board issued a waiver of informed consent and authorization to access, use, and disclose the data.
Patient identification
Patients were initially identified for inclusion in the analysis from administrative claims data, and final eligibility was based on medical chart review. Claims eligibility required diagnostic claims for CF (Supplemental Table) between 1 July 2008 and 31 May 2013 (patient identification period) and was defined as ≥1 inpatient (IP) claim with a diagnosis of CF in the primary position or ≥2 non-IP medical claims with a diagnosis of CF (with ≥1 claim in the primary diagnosis position) ≥ 30 days apart within a 12-month period. The most recent medical claim during the identification period with a CF diagnosis was chosen as the index date to observe the most recent period of care (Supplemental Figure). Patients were also required to have ≥18 months of continuous enrollment in a commercial health plan with medical and pharmacy benefits prior to and including the index date (patient observation period), be aged ≥6 years at study entry, and have no pharmacy claims for ivacaftor during the study period. The study was limited to patients six years of age and older because spirometry, as measured by forced expiratory volume in one second (FEV1), cannot be reliably measured in CF subjects younger than 6 yearsCitation16.
Among patients who met the claims eligibility criteria, a matching algorithm using the medical claims was used to identify their primary CF physician affiliated with a US CF Foundation Accredited Care Center. Physicians were sent a voluntary participation request letter requesting the physician’s support in arranging medical chart review of identified subjects. A professional chart abstraction firm was used to procure and abstract the medical charts. Medical charts from participating physicians were abstracted for a minimum of 18 months prior to and including the index date.
Charts valid for abstraction were required to contain ≥2 FEV1 test results and could not have evidence of patient participation in a phase 2/3 cystic fibrosis transmembrane conductance regulator (CFTR) modulator trial during the observation period; patient participation in a non-CFTR modulator phase 2/3 clinical trial did not invalidate charts for abstraction. Patients with medical claims for lung transplantation were removed post hoc from the final sample.
Measures
The 18-month patient observation period comprised a 6-month baseline period used to identify baseline demographic and clinical information and a 12-month follow-up period ending with the index date during which outcomes were assessed (Supplemental Figure).
Baseline patient characteristics
Demographic information (age and gender) was captured from claims data. Genotype, race/ethnicity, anthropometric measurements, and FEV1 were collected from charts. Percent predicted FEV1 (ppFEV1) in the baseline period was calculated according to Hankinson et al.Citation17 for adult patients and Wang et al.Citation18 for male patients up to 18 years and female patients up to 16 years. Baseline ppFEV1 was used to categorize patients by lung disease stage: severe (<40%), moderate (≥40% to <70%), or mild (≥70%)Citation19,Citation20. If patients had more than one baseline FEV1, the best ppFEV1 value was used in all analyses.
Outcomes
PEx during follow-up were ascertained from claims data using one or more of the following definitions: (1) a medical claim with a code for IV antibiotic; (2) an IP stay in which the stay had a diagnosis code in any position for CF with pulmonary manifestations or a diagnosis code in any position for a respiratory infection (e.g. pneumonia, Staphylococcus aureus) (Supplemental Table); or (3) a pharmacy claim for an oral antibiotic. This is consistent with previous definitions that have defined PEx by IV antibiotic treatmentCitation21–23 but goes beyond previous analyses to further define PEx associated with oral antibiotic useCitation8,Citation24,Citation25. Antibiotics used for chronic treatment, including azithromycin, inhaled tobramycin, inhaled colistin, and inhaled aztreonam, were not considered as an indication of PEx.
PEx episodes were considered to begin on an IP admission date, service date of a claim for an IV antibiotic, or service date for an oral antibiotic prescription fill. The end of a PEx episode was defined as the IP discharge date, IV antibiotic end date, or the run-out date of the supply of an oral antibiotic prescription claim (or the latest of these dates following multi-modal treatment), as long as this was followed by a period of ≥7 days in which no further claims suggesting an ongoing PEx episode were observedCitation5. This approach allowed the possibility that an individual PEx episode might be treated with more than one modality. PEx episode duration was calculated as the number of days from the start date to the end date.
PEx episodes were categorized by method of treatment: (1) PEx episodes requiring IV antibiotics and/or IP stay (PEx-IV); (2) PEx requiring IP stay (PEx-IP), which was a subset of a PEx-IV; and (3) PEx requiring oral antibiotics only (PEx-O). PEx episodes requiring IV antibiotics and PEx episodes requiring IP stay were grouped and reported together as a proxy for treatment of PEx with IV antibiotics (PEx-IV), to account for the inability to document IV antibiotics administered during IP stays in claims data and to provide a common basis for comparison with studies that defined a PEx as an episode requiring IV antibioticsCitation5,Citation23. Inpatient claims typically use revenue codes for reimbursement, which do not specify the type of medication that was taken (IV or otherwise). When available, typically in outpatient claims, IV antibiotics were identified using procedure codes on the medical claim.
PEx episode-level costs were calculated as all costs incurred for the duration of an episode. Annual costs attributable to PEx were calculated at the patient level as the total PEx costs incurred by a patient in the 12-month follow-up period. Costs were calculated as the sum of health plan and patient paid amounts, adjusted to reflect inflation between 2007 and 2013 and reported in 2013 dollarsCitation26.
Statistical analyses
Differences in baseline characteristics, PEx frequency, PEx count, and annual PEx-related costs stratified by lung disease stage were examined using chi-squared tests for categorical variables or one-way ANOVA for continuous variables. Analyses were conducted using the Statistical Analysis System (SAS version 9.2; SAS Institute, Cary, NC, USA) and Stata/SE (Stata Statistical Software: Release 12; StataCorp, College Station, TX, USA).
Risk factors for PEx were modeled focusing on PEx-IV outcome. A multivariate model using logistic regression was used to estimate the risk of ≥1 PEx-IV in the 12-month follow-up period. The initial list of covariates was identified based on statistically significant associations (p < 0.05) with PEx in univariate analysis. The variables were analyzed using forward selection, with manual retention of covariates based on statistical significance (p < 0.05) and clinical relevance. The final model is presented using a sequential approach to demonstrate how estimates of risk changed as new covariates were added to the model in which the first model included demographic variables, the second model added clinical characteristics, body mass index (BMI), and baseline ppFEV1, and the final model added a binary variable for the occurrence of ≥1 PEx-IV during the baseline period.
Results
Baseline characteristics
Of the 594 patients who met claims eligibility, valid charts from 158 providers were reviewed for 294 patients. The main reason eligible patients were not included was that the physician declined to participate (or did not respond to the request to provide the chart). After excluding patients with lung transplant and those lacking a baseline FEV1, 241 patients were included in this study (). Mean age was 23.9 years, with a nearly even distribution between male and female (). When using the best ppFEV1 value in the baseline period, the mean ppFEV1 for the overall sample was 82.2% and, when using the worst value, the mean was 75.3%. Among all 241 patients, 71.8% were categorized as having mild, 23.2% moderate, and 5.0% severe lung disease. Of 125 patients with genotype information, 44.8% were homozygous for the F508del mutation.
Figure 1. Patient identification. CF: cystic fibrosis; CFTR: cystic fibrosis transmembrane conductance regulator; FEV1: forced expiratory volume in 1 second; IP: inpatient stay. a300 charts were not abstracted because the physician declined to participate/provide the chart, the chart lacked ≥2 FEV1 measurements in the 18-month observation period, and/or there was evidence in the chart of patient participation in a phase 2/3 CFTR modulator trial.
Table 1. Baseline demographic and clinical characteristics.
Rate of PEx and PEx-related costs
The majority (88.0%) of patients experienced ≥1 PEx (any type), with a mean (median) rate of 2.90 (3.00) during the 12-month follow-up period (). Nearly half (48.1%) had ≥1 PEx-IV, with a mean (median) rate of 0.83 (0.00) during follow-up. The percentage of patients experiencing PEx-IV and the rate of PEx-IV increased with worsening lung disease.
Table 2. PEx frequency and mean annual PEx-related costs by disease stage during 12-month follow-up.
There were 698 PEx episodes in the 12-month follow-up period, of which 497 (71.2%) were PEx-O and 201 (28.8%) were PEx-IV; 141 (20.2%) were PEx-IP (a subset of PEx-IV). Mean episode duration for PEx-O was 18.8 days, compared with 28.6 days for PEx-IV (duration of PEx included the period of time over which all types of antibiotic treatment for PEx were administered) (). The mean costs per episode by method of treatment administration were notably different: $36,319 (median: $24,478; interquartile range [IQR]: $12,312–$42,616) for PEx-IV, $45,361 (median: $31,652; IQR: $21,195–$49,689) for PEx-IP, and $3265 (median: $1685; IQR: $287–$4557) for PEx-O (). As shown in , mean (median) annual costs attributable to PEx of any type were $37,025 ($10,833) among all patients and rose with stage of lung disease from $30,066 ($9456) among patients with mild disease to $119,862 ($48,263) among patients with severe disease; the increased cost was attributable to increases in the number of PEx-IV by disease stage ().
Figure 2. (A) Mean PEx episode duration (days ± SD) during follow-up. (B) Mean costs per PEx episode during follow-up. IP: inpatient; IV: intravenous; PEx: pulmonary exacerbation.
Risk factors for PEx
In the first model with age category and gender as covariates, the youngest age group (6–11 years) had a nearly 60% lower risk of experiencing a PEx-IV than patients aged 25 and older (reference group) (, model 1). However, when BMI and baseline ppFEV1 were added, age was no longer significant and higher baseline pulmonary function was associated with marginally lower risk of PEx-IV (, model 2). When the presence of ≥1 PEx-IV in the baseline period was added to the model with age category, gender, BMI, and baseline ppFEV1, baseline ppFEV1 remained a small but statistically significant predictor of PEx-IV risk, where every percentage point increase in baseline ppFEV1 reduced the risk of a PEx-IV in the following 12-month period by about 2% (, model 3). However, the strongest risk factor for PEx-IV during follow-up was the presence of ≥1 PEx-IV in the baseline period (odds ratio: 7.992; 95% confidence interval: 3.843, 16.621).
Table 3. Logistic regression models for risk of PEx requiring IV antibiotics and/or IP stay during 12-month follow-up.
Discussion
The results of this study demonstrate the significant economic burden of PEx in CF patients in the United States. PEx-related healthcare costs were categorized by stage of lung disease and method of treatment. Among all patients, 88.0% experienced PEx of any type and 48.0% required IV antibiotics and/or IP stay. Patients with worse pulmonary function were more likely to experience any type of exacerbation as well as exacerbations requiring IV treatment.
According to the US CF Foundation patient registryCitation23, 35% of patients were treated with IV antibiotics for a PEx in 2013, a percentage that was stable over the interval of this study (2008–2013) but varied widely across CF care centers. Patients in the current study were treated at a slightly higher rate: 48.0% of patients overall had a PEx-IV, with a mean of 0.83 exacerbations during 1-year follow-up. Compared with the registry patient population, a higher proportion of patients in this study were adults (62.3% vs. 46.4%–49.7% [2008–2013]), who are more likely to experience exacerbations requiring IV antibiotic treatment than pediatric patientsCitation8,Citation23. As expected, a higher frequency and rate of PEx-IV were also observed with worse disease stageCitation3,Citation4. Notably, when treatment with only oral antibiotic therapy was added to the definition of PEx, 88.0% of patients experienced an exacerbation at a rate of 2.9 per year. Overall, 71.0% of PEx episodes were treated with oral antibiotics only. Our results suggest that either oral antibiotic treatment is becoming more common (during 2003–2005, 45.5% of PEx were treated with only oral antibiotics in North American care centersCitation8), or our definition of oral antibiotic prescription is detecting more, or overestimating the number of, PEx-O.
A baseline PEx-IV was the strongest predictor of future PEx-IV, increasing risk eight-fold. These results parallel previous analyses in which prior exacerbations treated with IV antibiotics dominated all other demographic and clinical predictorsCitation27. As with previous studies, we found that a higher baseline ppFEV1 remained a significant but small predictor of lower risk even when baseline PEx-IV was included in the modelCitation5,Citation27.
The mean cost per PEx episode was $12,784 but ranged from $3265 to $45,361 depending on IV or oral antibiotic administration. The mean cost for a PEx-IV episode was $36,319, more than ten-fold higher than PEx-O. Annual costs attributable to PEx averaged $37,025 per patient and increased sharply with worsening disease stage, from $30,066 among patients with mild lung disease to $119,862 among patients with severe lung disease, which reflects the higher rate of PEx-IV among patients with lower lung function and greater costs of PEx-IV episodes. These results complement previous work reporting a direct relationship between total healthcare costs and CF disease stageCitation13,Citation20. Studies of US healthcare costs among CF patients treated in clinical practice have focused primarily on all-cause costs (including CF- and non-CF-related etiologies)Citation10,Citation12 or all CF-related costsCitation11, rather than exacerbation-specific costs. In 2006 US dollars, annual all-cause costs averaged $46,000 per patientCitation12, or approximately 25% more than the 2013 annual costs observed in the current study solely for treatment of any type of PEx. O’Sullivan et al. estimated CF-related costs among patients with pulmonary manifestations during 2002–2006Citation11: the total CF-related medical costs accounted for roughly $29,000 in annual expenditures, which is 64% of the costs observed in this current study for a single PEx episode requiring IP stay. While estimates of mean annual costs are important to understand overall disease burden, they do not provide sufficient insight into specific high-cost events such as PEx. The frequency and costs of PEx observed in this study underscore the need to develop new strategies to prevent PEx.
The results of this study should be considered in the context of certain limitations. This was a retrospective, observational study using a convenience sample of 241 patients whose medical charts were available for abstraction. Thus, there is potential for selection bias. Administrative claims data were used to identify PEx because medical chart data was were incomplete. However, there are no standard diagnosis or procedure codes in claims data to identify PEx. In addition, it was assumed that IP stays with diagnosis codes for CF with pulmonary manifestations or respiratory infections included IV antibiotic treatment of PEx, even though antibiotic administration during an IP stay is typically not documented because inpatient claims do not typically specify drugs administered in a hospital. Inclusion of oral antibiotics may overestimate the presence of PEx if they are used to treat nonpulmonary infections (e.g. otitis media). Oral antibiotics typically used for chronic treatment (e.g. azithromycin) were excluded, but it is possible that some patients were being treated chronically with other oral antibioticsCitation23. These limitations may have led to under- or over-estimation of the true number of PEx. Finally, among the 241 patients with available baseline FEV1, only a small number of patients (5%) had severe disease, which may limit the generalizability of results for the severe disease cohort. Patients included in the study had commercial coverage from a large US health insurer. Thus, the results may not be generalizable to patients with Medicaid coverage and other forms of insurance or to the uninsured. Our cost results cannot be readily compared to studies outside of the United States due to underlying differences in healthcare delivery systemsCitation20,Citation28,Citation29. However PEx are common in CF, and the impact of disease stage and method of treatment administration observed in this study should be similar elsewhere.
Conclusions
Most patients aged 6 years and older with CF experienced ≥1 PEx annually, and nearly half received treatment with IV antibiotics and/or IP stay. A recent history of PEx-IV increased future risk of PEx-IV eight-fold. Annual healthcare costs attributable to PEx were four-fold higher among patients with severe disease compared with patients with mild disease. Given the direct impact of PEx on healthcare costs as well as the impact on pulmonary function and increased risk of future exacerbations, reducing the frequency of PEx should be a key target for future CF therapies.
Transparency
Declaration of funding
This study was funded by Vertex Pharmaceuticals Incorporated. Vertex Pharmaceuticals Incorporated contracted with Optum to perform this study.
Author contributions: All authors were involved in the conception and design of the study, analysis and interpretation of the data, and the drafting, revision and final approval of the manuscript. All authors agree to be accountable for all aspects of the study.
Declaration of financial/other relationships
P.S.H. and J.L.R. have disclosed that they are employees of Vertex Pharmaceuticals Incorporated and may own stock or stock options in that company. S.T. and A.W. have disclosed that they are employees of Optum, which was funded by Vertex Pharmaceuticals Incorporated. J.S.W. has disclosed that he was previously employed by Vertex Pharmaceuticals Incorporated and is currently an employee of the University of Colorado Medical School and a paid consultant of Vertex Pharmaceuticals Incorporated. M.S.S. has disclosed that he is an employee of Virginia Commonwealth University and a paid consultant of Vertex Pharmaceuticals Incorporated.
CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Supplemental_material.docx
Download MS Word (125.9 KB)Acknowledgments
Medical writing and editorial support were provided by Optum, Jeremy Kennard, PhD and Dena McWain of Ashfield Healthcare Communications, and funded by Vertex Pharmaceuticals Incorporated. Editorial coordination and support was provided by Dhrupad Patel, PharmD who is an employee of Vertex Pharmaceuticals Incorporated and may own stock or stock options in that company.
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