Introduction {#Sec1}
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Asthma is a common respiratory condition which affects approximately 7.4% of the US adult population and 8.6% of the US pediatric population \[[@CR1]\]. The condition is characterized by airway inflammation which can lead to recurrent episodes of exacerbations and cause symptoms of wheezing, breathlessness, chest tightness, and coughing \[[@CR2], [@CR3]\]. These episodes of exacerbations often require treatment with a corticosteroid to reduce airway inflammation, and patients with worsening symptoms are commonly treated in the hospital or emergency department (ED) \[[@CR4], [@CR5]\]. In the US, asthma exacerbations result in 15 million outpatient visits, 2 million ED visits, and 500,000 inpatient admissions annually \[[@CR5]\]. The annual direct and indirect cost of asthma care in the US is around \$56 billion \[[@CR6]\].

Medications administered by metered dose inhalers (MDIs), such as inhaled corticosteroids (ICS) and bronchodilators, are the mainstay of long-term control asthma treatment to prevent the occurrence of exacerbations \[[@CR5], [@CR7], [@CR8]\]. However, patients with poor hand-breath actuation coordination may have difficulty in using MDIs properly and can remain vulnerable to exacerbations \[[@CR5], [@CR9]\]. Valved holding chambers (VHCs) are designed to reduce oropharyngeal deposition by substantially changing the aerodynamic particle size distribution of the inhaled aerosol, and can assist in improving drug delivery to the lungs by holding the aerosol plume of medication-loaded particles until the patient is ready to inhale, eliminating the need to carefully coordinate the timing of MDI actuation and inhalation \[[@CR10], [@CR11]\]. A recent study assessing the relationship between asthma control and patient ability to use their MDIs found that patients who used a spacer with their MDIs had significantly better asthma control compared to those who used MDIs alone \[[@CR12]\]. However, the effectiveness of VHCs and other spacer devices can be adversely affected by electrostatic charge, a commonly reported cause of inconsistent medication delivery \[[@CR13]\].

Valved holding chamber (VHC) devices made of antistatic materials offer a potential solution by reducing dose variability related to electrostatic charge, and may in theory help improve asthma control in patients who use VHCs to assist with aerosolized drug delivery \[[@CR13], [@CR14]\]. A laboratory investigation by Suggett et al. found that antistatic VHCs delivered more respirable medication from the MDI compared to non-antistatic VHCs, in part due to the antistatic nature of the materials \[[@CR15]\]. However, no clinical or real-world studies have evaluated the effects of an antistatic VHC on asthma outcomes. The AeroChamber Plus^®^ Flow Vu^®^ Antistatic Valved Holding Chamber (AC^+^FV AVHC) is an antistatic VHC designed to be used with pressurized MDIs to administer aerosolized medication in patients who may have difficulty with the coordination and control involved in using MDIs correctly. An additional benefit of the AC^+^FV AVHC is the incorporation of an inspiratory flow indicator (IFI) for the patient/caregiver to observe effective inhalation. The IFI provides real-time feedback confirming an effective inhalation and ensures that there are no leakages of ambient air into the space between facemask and face that could prevent medication delivery altogether \[[@CR16], [@CR17]\]. The objective of this study was to compare the effects of the antistatic AC^+^FV AVHC and non-antistatic control VHCs on treatment outcomes, resource use, and healthcare costs in a real-world asthma population.

Methods {#Sec2}
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This retrospective database study used data from the QuintilesIMS Real-World Data Adjudicated Claims Database (formerly known as PharMetrics Plus). The database contains adjudicated medical and pharmacy claims for more than 150 million US health plan members from 2006 onwards. The data are patient-level, longitudinal, and representative of the US commercially insured population. The database covers 90% of US hospitals, 80% of all US doctors' offices, and relate to 85% of Fortune 100 employees. Inpatient and outpatient diagnoses are recorded as International Classification of Diseases (ninth and tenth revisions) Clinical Modification (ICD-9/10-CM) codes. Data include inpatient and outpatient procedures, dates of service, retail and mail-order claims, inpatient stay, and provider specialty. Amounts allowed and paid by health plans are available for all services provided along with the dates of service for all claims. Other data elements available include demographic information (patient age, gender, and geographical region), product type (e.g., health maintenance organization and preferred provider organizations), payer type (e.g., commercial and self-insured), and start and stop dates of health plan enrollment.

Patients were selected for the study if they were treated with an AC^+^FV AVHC or a non-antistatic VHC (control VHC) between January 1, 2010 and August 31, 2015 (the "selection window"). The date of the first VHC device within the selection window was defined as the index date. All patients had to be treated with a long-term controller medication \[inhaled corticosteroid (ICS) or fixed-dose combination of ICS and long-acting β2 agonist (ICS/LABA)\] MDI within 60 days before or 60 days after the index date. All patients had at least 12 months of continuous healthcare coverage before the index date ("preindex period"), were diagnosed with asthma (ICD-9: 493.x) on index date or during the preindex period, and had at least 30 days of continuous healthcare coverage after the index date ("post-index period"). Patients were excluded if they had incomplete age, gender, or payer information; had a diagnosis of COPD (ICD-9: 490.x, 491.x, 492.x, 494.x, 495.x, and 496.x) on the index date or during the preindex period; or discontinued their long-term control MDI before index. In order to ensure that patients were newly treated with an AC^+^FV AVHC or control VHC, patients treated with AC^+^FV AVHC were excluded if they had evidence of non-AC^+^FV AVHC use (antistatic or control VHC) at any time during the study or AC^+^FV AVHC use during the preindex period. Patients treated with control VHC were excluded if they had evidence of any antistatic VHC use at any time during the study, or had control VHC use during the preindex period. Patients were categorized into mutually exclusive cohorts (AC^+^FV AVHC cohort or control VHC cohort) based on the type of VHC at the index date.

In order to reduce pretreatment confounders between the cohorts, patients in the AC^+^FV AVHC cohort were propensity score (PS) matched to patients in the control VHC cohort at a 1:1 ratio using a greedy matching algorithm without replacement \[[@CR18]\]. Patients were matched on baseline age categories (0--2, 3--5, 6--12, 13--17, 18--34, 35--44, 45--54, 55--64, 65--74, 75 or older), gender, geographic region (Northeast, Midwest, South, West), Charlson comorbidity index (CCI) category (0, 1, 2, 3, 4+) \[[@CR19]\], comorbid conditions \[attention deficit hyperactivity disorder (ADHD), allergic rhinitis, anemia, anxiety, cancer, bronchopneumonia, cardiac disease, cerebrovascular disease, depression, diabetes, hypertension, obesity, other vascular diseases, pneumonia, pulmonary hypertension, and respiratory infection\], medication history \[ICS, short-acting β2 agonist (SABA), LABA, fixed-dose ICS/LABA and oral corticosteroids (OCS)\], type of MDI (ICS or fixed-dose ICS/LABA), history of respiratory support including oxygen therapy and mechanical ventilation, history of severe exacerbations, history of moderate exacerbations, and history of all-cause hospitalizations. Patients without appropriate matches were not included in the analysis.

Treatment outcomes included number of patients with asthma exacerbations (moderate to severe); number of exacerbations per patient at 1, 6, 9, and 12 months after the index date; and time (days) to the first exacerbations. These measures were reported for patients with at least 12 months of post-index follow-up. Exacerbation severity was defined according to the literature \[[@CR20]--[@CR22]\]. A moderate exacerbation was defined as an ED visit claim (not leading to a hospital admission) with an asthma diagnosis, or an OCS prescription fill within 30 days of a physician visit with an asthma diagnosis; a severe exacerbation was defined as an inpatient admission claim with an asthma diagnosis. Furthermore, the incidence rate (IR) of exacerbations (either moderate or severe) was measured for patients with at least 30 days of post-index follow-up. The IR was defined as the number of patients with an event divided by total time spent at risk, which was from the index date to the end of enrollment, the end of the study period, discontinuation of index treatment (at least 60 days between the end of the supply and the next prescription fill), or the occurrence of an event---whichever occurred first during the variable follow-up. Asthma-related healthcare resource use measures included hospitalizations, outpatient visits, ED visits, laboratory tests, and ancillary and other services based on medical claims with an asthma diagnosis as well as prescriptions for an asthma medication. Asthma-related costs associated with these resources were also reported. Healthcare resource use and cost measures over 12 months of follow-up were reported for patients with at least 12 months of post-index follow up. The use of a fixed follow-up period was required to ensure a fair comparison of these measures between the two cohorts.

Baseline patient characteristics were reported using descriptive statistics, with frequency (*n*, %) for categorical measures and mean, standard deviation (SD), median, minimum, and maximum values for continuous variables. Treatment outcomes, healthcare resource use measures, and related costs in the AC^+^FV AVHC cohort and matched control VHC cohort were compared using bivariate chi-square tests for proportions and Student's *t* test for means. The numbers of moderate-to-severe exacerbations per patient in the AC^+^FV AVHC and control VHC cohorts were also compared using rate ratios, defined as the number of moderate-to-severe exacerbations per patient in the antistatic VHC cohort divided by the number of moderate-to-severe exacerbations per patient in the control VHC cohort. The proportions of patients without an exacerbation in the AC^+^FV AVHC cohort and the control VHC cohort were compared using a Kaplan--Meier estimation of time to first occurrence of a moderate-to-severe exacerbation. In addition to the*t* test of differences in the mean costs of the two matched sample, a regression analysis was performed in the unmatched population to confirm the results of the bivariate analysis of healthcare costs in the matched population. In the regression analysis, the marginal effect of AC^+^FV AVHC on per-patient costs for moderate-to-severe exacerbations was measured using generalized linear models (GLMs) with a log link and gamma family distribution, along with covariate adjustments to control for potential confounders. All inferential statistical analyses were conducted assuming a two-tailed test of significance and a alpha level set a priori at 0.05. All analyses were conducted using SAS 9.4 (Cary, NC, USA).

No institutional review board (IRB) review was required for this retrospective cohort analysis using HIPAA-compliant de-identified patient data.

Results {#Sec3}
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Demographics and Clinical Characteristics {#Sec4}
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There were 156,801 patients treated with the AC^+^FV AVHC in the database within the selection window. After applying the selection criteria, 13,995 antistatic VHC patients were retained. After PS matching, a total of 9325 antistatic VHC patients and 9325 control VHC patients were identified for the analyses (Table [1](#Tab1){ref-type="table"}).Table 1Selection of patients for the AC^+^FV AVHC cohortSelection criteriaExcludedRemaining*N*%*N*%Inclusion criteria Evidence of the AC^+^FV AVHC between January 1, 2010 through August 31, 2015 (the date of first antistatic VHC was defined as the index date)----156,801100.0 Evidence of MDI use 60 days before or after index AC^+^FV AVHC claim111,67271.245,12928.8 Continuous enrollment for ≥30 days after index date (post-index follow-up was variable)35152.241,61426.5 Meeting requirements for continuous enrollment before index date (preindex period)11,5327.430,08219.2 ≥1 diagnosis of asthma during the preindex period or on index date91115.820,97113.4Exclusion criteria Incomplete data (age, gender, payer)130.120,95813.4 Evidence of any VHC other than the AC^+^FV AVHC use at any time during the study period45482.916,41010.5 Evidence of any antistatic VHC use in the preindex period1770.116,23310.4 Diagnosis of COPD during the preindex period or on the index date19301.214,3039.1 Discontinuation of long-term control MDI before index3480.213,9558.9

Table [2](#Tab2){ref-type="table"} shows baseline demographic and clinical characteristics for the AC^+^FV AVHC and control VHC cohorts. The cohorts were balanced on all baseline characteristics (*p* values \>0.05). The mean age was 12.2 years, and the majority of patients were 17 years or younger. All patients had at least one comorbidity (CCI score ≥1), and the most common comorbidities were respiratory infection (≥68.7%), allergic rhinitis (≥40.3%), and pneumonia (≥12.4%). The majority of the patients were prescribed an ICS (≥87.1%) and/or SABA (≥85.3%) on or prior to the index VHC, and half of the patients were prescribed an OCS (≥50.3%). Most patients used their index VHC with an ICS (≥93.0%). Prior to the index VHC, less than half of the patients had a moderate exacerbation (≥45.0%), and fewer had a severe exacerbation (≥4.4%) or an all-cause hospitalization (≥6.0%). Very few patients were on oxygen therapy or mechanical ventilation (≥0.2%).Table 2Baseline characteristicsDemographic and clinical characteristicsAC^+^FV AVHCControl VHC*p* value*N* = 9325*N* = 9325*N*(%)*N*(%)Age on index date (years) Mean ± SD12.23 ± 13.6512.24 ± 13.750.7405 Median88Age category (years) 0--25796.2%6026.5%0.1577 3--5232624.9%232424.9%0.9347 6--12411544.1%412444.2%0.7517 13--1798310.5%97010.4%0.5903 18--344655.0%4614.9%0.8453 35--442702.9%2462.6%0.1783 45--642823.0%2833.0%0.9573 55--642302.5%2392.6%0.6280 65--74640.7%570.6%0.5175 75 or older110.1%190.2%0.1167 0--17800385.8%802086.0%0.6021 18 or older132214.2%130514.0%0.6021Gender Female413444.3%410144.0%0.3369 Male519155.7%522456.0%0.3369Geographic region Northeast347737.30%346037.10%0.1693 West243026.10%246826.50%0.1462 Midwest190720.50%191420.50%0.7876 South151116.20%148315.90%0.0695Charlson comorbidity index (CCI)^\#^ Mean ± SD1.05 ± 0.361.05 ± 0.330.5829 Median11 000.0%00.0%NA 1902196.7%903196.8%0.6604 21761.9%1721.8%0.8214 3860.9%850.9%0.9372 4+420.5%370.4%0.5737Comorbid conditions Respiratory infection641168.80%640568.70%0.8585 Allergic rhinitis376240.30%377140.40%0.7901 Pneumonia115412.40%116712.50%0.6427 Anxiety4364.70%4044.30%0.1613 ADHD4284.60%4164.50%0.5699 Obesity3784.10%3143.40%0.0041 Depression3043.30%2773.00%0.2076 Hypertension2943.20%2863.10%0.7061 Cardiac disease2462.60%2072.20%0.0538 Anemia2152.30%1922.10%0.1878 Other vascular diseases1771.90%1541.70%0.1820 Cancer1651.80%1451.60%0.2418 Diabetes1101.20%1151.20%0.7295 Cerebrovascular disease380.40%400.40%0.8185 Pulmonary hypertension120.10%70.10%0.2513Asthma medication history ICS811887.10%811887.10%1.000 SABA795385.30%795385.30%1.000 OCS475451.00%469350.30%0.0784 Fixed-dose (LABA/ICS) combination6847.30%6847.30%1.000 LABA170.20%190.20%0.7389Index MDI (including 60 days post-index) ICS869093.2%867693.0%0.3293 Fixed-dose (LABA/ICS) combination6356.8%6497.0%0.3293History of respiratory support Oxygen therapy/mechanical ventilation230.2%290.3%0.3961History of severe exacerbation4334.6%4084.4%0.2443History of moderate exacerbation425545.6%419745.0%0.0891History of any-cause hospitalization5976.4%5626.0%0.1668

Occurrence of Moderate-to-Severe Exacerbations {#Sec5}
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Among patients with at least 30 days of follow-up (*n* = 9325 for each cohort), the incidence rate of moderate-to-severe exacerbations per 100 person-days (95% CI) was significantly higher in the control VHC cohort than in the AC^+^FV AVHC cohort \[0.161 (0.150--0.172) vs. 0.137 (0.128--0.147)\] (Table [3](#Tab3){ref-type="table"}). Average time from the index date to the first moderate-to-severe exacerbation was 141.9 (SD ±106.87) days for the AC^+^FV AVHC cohort and 135.7 (SD ±107.62) days for the control VHC cohort (*p* = 0.2714). The Kaplan--Meier curve of time to moderate-to-severe exacerbation revealed that the proportion of exacerbation-free patients was greater in the AC^+^FV AVHC cohort than the control VHC cohort throughout the study period (chi square = 12.05, *DF* = 1.00, *p* \< 0.05; Fig. [1](#Fig1){ref-type="fig"}).Table 3Incidence rates of moderate or severe exacerbations for patients with at least 30 days of follow-upTreatment groupNumber of patients with a moderate or severe exacerbationTotal person days at riskIncidence rate95% CIAC^+^FV AVHC (*N* = 9325)1160737,3920.14\[0.128, 0.147\]Control VHC (*N* = 9325)1292710,2690.16\[0.150, 0.172\] Fig. 1Kaplan--Meier curve for time to exacerbation

Table [4](#Tab4){ref-type="table"} shows the occurrence of moderate-to-severe exacerbations among the subgroup of patients with at least 12 months of follow-up. Among the 4293 patients in each cohort, 29.5% of the AC^+^FV AVHC patients (*n* = 1265) and 30.6% of the control VHC patients (*n* = 1314) had at least one moderate-to-severe exacerbation during the study period (*p* = 0.2487). Mean number of moderate-to-severe exacerbations per patient at 1 month was 0.07 (SD ±0.34) for AC^+^FV AVHC and 0.08 (SD ±0.34) for control VHC (*p* = 0.0944); mean number of moderate-to-severe exacerbations per patient at 12 months was 0.54 (SD ±1.17) for AC^+^FV AVHC and 0.60 (SD ±1.30) for control VHC (*p* = 0.0674). Patients using the AC^+^FV AVHC had a significantly lower number of moderate-to-severe exacerbations compared to those using the control VHC both at 6 months \[0.29 (SD ±0.78) for AC^+^FV AVHC and 0.33 (SD ±0.86) for control VHC; *p* \< 0.05\] and at 9 months \[0.42 (SD ±0.99\] for AC^+^FV AVHC and 0.47 (SD ±1.09) for control VHC; *p* \< 0.05\]. The rate ratios throughout the 12-month follow-up period (0.88--0.90) consistently showed that patients with AC^+^FV AVHC use were 10--12% less likely to experience a moderate-to-severe exacerbation compared to patients with control VHC use. The mean number of moderate-to-severe exacerbations per patient at each time point in each cohort is shown in Fig. [2](#Fig2){ref-type="fig"}.Table 4Occurrence of exacerbations (moderate to severe) among patients with at least 12 months of follow-upOccurrence of exacerbationAC^+^FV AVHCControl VHCRate ratio*p* value*N* = 4293*N* = 4293Patients with at least one exacerbation*n* (%)1265 (29.5)%1314 (30.6)%--0.2487Exacerbations per patient (mean ± SD) At 30 days0.07 ± 0.340.08 ± 0.340.880.0944 At 6 months0.29 ± 0.780.33 ± 0.860.880.0216 At 9 months0.42 ± 0.990.47 ± 1.090.900.0463 At 12 months0.54 ± 1.170.60 ± 1.300.900.0674Time to exacerbation (days) Mean ± SD141.9 ± 106.87135.7 ± 107.62--0.2714 Fig. 2Moderate-to-severe exacerbations per patient at 30 days, 6 months, 9 months, and 12 months

Asthma-Related Healthcare Resource Use {#Sec6}
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In Table [5](#Tab5){ref-type="table"} it can be seen that, over 12 months of follow-up, a small proportion of the patients had an asthma-related hospitalization in both cohorts (3.0% for AC^+^FV AVHC vs. 3.7% for control VHC; *p* = 0.0702). The average number of hospitalizations per patient was 0.04 for both cohorts (*p* = 0.2041). The majority of the patients visited a doctor's office (≥86.8%; *p* = 0.7990) at a rate of ≥2.7 visits per patient (*p* = 0.2775). The proportion of patients visiting the ED was significantly lower in the AC^+^FV AVHC cohort than in the control VHC cohort (10.8% vs. 12.4%; *p* \< 0.05), and the number of ED visits per patient was also significantly lower in the AC^+^FV AVHC cohort compared to the control VHC cohort (0.15 visits vs. 0.18 visits; *p* \< 0.05). All patients in both groups had at least one asthma-related pharmacy fill, with 6.9 fills per patient for the AC^+^FV AVHC cohort and 7.1 fills per patient for the control VHC cohort (*p* = 0.2350).Table 5Healthcare resource useUtilization measuresAC^+^FV AVHCControl VHC*p* value*N* = 4293*N* = 4293Hospitalizations Patients with at least 1 hospitalization (*n*, %)127 (3.0)%157 (3.7)%0.0702 Hospitalizations per patient (mean, SD)0.04 ± 0.220.04 ± 0.230.2041Outpatient visits Patients with at least 1 outpatient visit (*n*, %)3720 (86.7)%3728 (86.8)%0.7990 Outpatient visits per patient (mean, SD)2.67 ± 3.172.75 ± 3.270.2775ED visits Patients with at least 1 ED visit (*n*, %)462 (10.8)%533 (12.4)%0.0167 ED visits per patient (mean, SD)0.15 ± 0.510.18 ± 0.580.0026Pharmacy fills Patients with at least 1 pharmacy fill (*n*, %)4293 (100.0)%4293 (100.0)%NA Fills per patient (mean, SD)6.91 ± 4.627.08 ± 4.800.2350

Moderate-to-Severe Exacerbation-Related Cost {#Sec7}
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The per patient cost associated with a moderate-to-severe exacerbation for the AC^+^FV AVHC patients and the control VHC patients was \$78.39 (SD ±\$1769.38) and \$68.17 (SD \$±1057.83; *p* = 0.1976) at 30 days, \$259.96 (SD ±\$3116.38) and \$321.16 (SD ±\$4704.31; *p* = 0.0983) at 6 months, \$393.01 (SD ±\$3969.09) and \$444.60 (SD ±\$5003.96; *p* = 0.1391) at 9 months, and \$514.25 (SD ±\$4259.03) and \$544.07 (SD ±\$5257.33; *p* = 0.1455) at 12 months (Table [6](#Tab6){ref-type="table"}).Table 6Moderate-to-severe exacerbation costsCost per patientAC^+^FV AVHCControl VHC*p* value*N* = 4293*N* = 4293Moderate-to-severe exacerbation cost per patient (mean ± SD) At 30 days\$78.39 ± \$1769.38\$68.17 ± \$1057.830.1976 At 6 months\$259.96 ± \$3116.38\$321.16 ± \$4704.310.0983 At 9 months\$393.01 ± \$3969.09\$444.60 ± \$5003.960.1391 At 12 months\$514.25 ± \$4259.03\$544.07 ± \$5257.330.1455

In the regression model, the cost of treating a moderate-to-severe exacerbation was found to be significantly lower for the AC^+^FV AVHC patients than for the control VHC patients at 30 days (23% lower; *p* \< 0.05), at 6 months (25% lower; *p* \< 0.05), at 9 months (20% lower; *p* \< 0.05), and at 12 months (12% lower; *p* \< 0.05) (Table [7](#Tab7){ref-type="table"}).Table 7Marginal effect of AC^+^FV AVHC on exacerbation-related costsParameterParameter estimateExp (b)Standard error*p* valueCost of exacerbation in the AC^+^FV AVHC group at 30 days from index date−0.260.770.04\<0.0001 Reference: control VHC groupCost of exacerbation in the AC^+^FV AVHC group at 6 months from index date−0.290.750.04\<0.0001 Reference: control VHC groupCost of exacerbation in the AC^+^FV AVHC group at 9 months from index date−0.230.800.04\<0.0001 Reference: control VHC groupCost of exacerbation in the AC^+^FV AVHC group at 12 months from index date−0.130.880.040.0017 Reference: control VHC group

Discussion {#Sec8}
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This is the first real-world study comparing an AC^+^FV AVHC with control non-antistatic VHCs. Findings from this study add to the body of literature supporting the benefits of using VHCs with inhaler medications for treating asthma \[[@CR23], [@CR24]\]. The addition of VHCs can help make hand-held inhalers easier to use, especially for patients who have difficulty using MDIs. Asthma disease control is highly associated with drug delivery to the lungs, and the use of VHCs can help improve deposition of asthma medications into the lower respiratory tract compared to MDIs alone. Moreover, an antistatic VHC could result in better drug delivery compared to non-antistatic VHCs by limiting the electrostatic charge in the chamber and increasing the amount of aerosol cloud available for deposition to the lungs \[[@CR25]\].

In our study, about 29.5% of the patients in the AC^+^FV AVHC group experienced at least one moderate-to-severe exacerbation in the 12-month follow-up period (30.6% of patients in the control VHC group), which is slightly lower than the proportion of patients with an exacerbation (34.4%) reported in a previously published retrospective database study conducted in a similar patient population \[[@CR26]\]. That study also reported a mean of 1.40 exacerbations per patient per year in females and a mean of 1.43 exacerbations per patient per year in males on ICS therapy, as well as 1.42 exacerbations per patient per year in females and 1.40 exacerbations per patient per year in males on ICS/LABA therapy \[[@CR26]\]. In comparison, our study reports fewer exacerbations per patient (0.54 moderate-to-severe exacerbations per patient in the AC^+^FV AVHC group at 12 months and 0.60 moderate-to-severe exacerbations per patient in the control VHC group at 12 months). The rate ratios of exacerbations between the two cohorts show that the likelihood of patients in the AC^+^FV AVHC group experiencing a moderate-to-severe exacerbation trends lower than that for the control VHC group throughout the follow-up period, suggesting that adding the AC^+^FV AVHC to an MDI may help improve the management of asthma exacerbations compared to adding a control VHC.

Additionally, among patients with at least 30 days of follow-up, we found that the AC^+^FV AVHC group had a significantly lower incidence rate of moderate-to-severe exacerbations than the control VHC group. This has potential implications for early treatment outcomes in asthma such as controlling future exacerbations because previous exacerbations have been reported to be a risk factor for future exacerbations \[[@CR27], [@CR28]\]. The difference in exacerbation trends, which was sustained over 12 months according to the Kaplan--Meier analysis, suggests that patients using the AC^+^FV AVHC may experience better and sustained outcomes than those using a control VHC type. Since exacerbations are acute events which often require unscheduled healthcare resource utilization, the utilization of ED following treatment initiation can be used as a surrogate marker for assessing the effect of treatment on the occurrence of exacerbations \[[@CR29]\]. Our analysis demonstrated that the rate of ED visits per patient in the AC^+^FV AVHC group was significantly lower than that in the control VHC group in the follow-up. This finding supports the additional study observation that exacerbation events in the AC^+^FV AVHC group were consistently lower than in the control VHC group in real-world data. The lower occurrence of asthma-related ED visits observed in the AC^+^FV AVHC group may lead to an expectation that the proportion of patients with an asthma-related hospitalization would also be smaller in the AC^+^FV AVHC group compared to the control group. Nonetheless, despite the slightly lower proportion observed (3.0% vs. 3.7%), the differences did not reach a statistically significant level.

Exacerbations are associated with high healthcare resource use and consequently the high economic burden of asthma \[[@CR29]\]. An administrative claims database study found that patients with exacerbations had a mean per patient healthcare cost of \$4212 more than those without an exacerbation \[[@CR20]\]. Therefore, controlling exacerbations is important. No significant differences in the cost associated with a moderate-to-severe exacerbation were observed between AC^+^FV AVHC patients and control VHC patients when the mean costs were compared. This could be partly the result of the high degree of skewness in the cost data. Our alternative analysis using the regression model in the unmatched cohorts, adjusting for potential confounders and addressing the issues of outliers and heavy-tailed cost data, however, showed statistically significantly lower exacerbation-related costs associated with the AC^+^FV AVHC compared to the control VHC at 30 days, 6 months, 9 months, and 12 months. This finding suggests that the AC^+^FV AVHC may well help reduce exacerbation-related costs when compared to control VHCs.

As mentioned in the "[Introduction](#Sec1){ref-type="sec"}," there are laboratory studies which support the hypothesis that, in a real-world setting, medication delivery via an antistatic VHC would be closer to optimal and more consistent than delivery via a non-antistatic VHC. Our study appears to provide some real-world validation of that hypothesis in terms of asthma control; however, we recognize that the presence of the inhalation feedback indicator in the AC^+^FV AVHC may also have contributed to the observed outcome differences.

There are inherent limitations to the use of secondary data and observational study methods that should be considered when interpreting results. The adjudicated claims database does not report clinical disease information (e.g., lung function, symptoms, etc.) and it was not possible to define severity by clinical markers; patients were diagnosed using ICD codes created for billing. Training for the proper use of the device from providers as well as adherence to device use is important for attaining benefits from devices; however, this information was not available in our database. The database contains commercially insured patients and our findings may not be generalizable to the Medicare or Medicaid population.

There are, however, several strengths of our study. Since the QuintilesIMS Real-World Data Adjudicated Claims Database is representative of the US commercially insured population, the results from our study are generalizable to the commercially insured US population. The cost and utilization analyses performed in our study involved fully adjudicated claims data on healthcare services (hospitalizations, ED, outpatient, pharmacy, and other services) and all associated costs. The study also employed PS matching, which addressed the issue of multicollinearity in observational studies, since covariates may be highly correlated (e.g., age and comorbidities).

Conclusions {#Sec9}
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The AeroChamber Plus^®^ Flow Vu^®^ Antistatic VHC was associated with delayed time to first exacerbation, a lower occurrence of asthma-related ED visits, and lower exacerbation-related costs when compared to control non-antistatic VHCs. Exacerbation rates also trended lower for the AC^+^FV AVHC throughout the 12-month study period. Findings from our study therefore suggest that the use of the AC^+^FV AVHC in association with a pMDI may result in better asthma control compared to the use of non-antistatic VHCs.

**Enhanced content**

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Sponsorship for this study and article processing charges was funded by Trudell Medical International.

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.

Disclosures {#FPar1}
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Chakkarin Burudpakdee received compensation from Trudell Medical International. Dominic Coppolo is an employee of Monaghan Medical Corporation, who marketed the AeroChamber Plus^®^ Flow Vu^®^ Antistatic Valved Holding Chamber in the US. Jason Suggett is an employee of Trudell Medical International. Vladimir Kushnarev is an employee of Trudell Medical International.

Compliance with ethics guidelines {#FPar2}
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No institutional review board (IRB) review was required for this retrospective cohort analysis using HIPAA-compliant, de-identified patient data.

Data availability {#FPar3}
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The datasets generated during and/or analyzed during the current study are not publicly available due to the commercially owned, proprietary nature of the datasets, but are available from the corresponding author on reasonable request.

Open Access {#FPar4}
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This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (<http://creativecommons.org/licenses/by-nc/4.0/>), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
