Metered-dose inhalers vs nebulization for the delivery of albuterol in pediatric asthma exacerbations: A cost-effectiveness analysis in a middle-income country.

OBJECTIVES: Although the benefits of albuterol delivered via metered-dose inhalers with a spacer (MDI+S) have been increasingly recognized, the evidence regarding the cost-effectiveness of MDI+S compared to nebulization (NEB) is not sufficient, especially in less-affluent countries, where the clinical and economic burden of the disease is the greatest. The aim of the present study was to evaluate the cost-effectiveness of MDI+S vs NEB for delivering albuterol for the treatment of pediatric asthma exacerbations. METHODS: A decision-analysis model was developed to estimate the cost-effectiveness of MDI+S vs NEB for delivering albuterol for the treatment of pediatric asthma exacerbations. Effectiveness parameters were obtained from a systematic review of the literature. Cost data were obtained from hospital bills and from the national manual of drug prices in Colombia. The study was carried out from the perspective of the national healthcare system in Colombia, a middle-income country (MIC). The main outcome of the model was the avoidance of hospital admission. RESULTS: For the base-case analysis, the model showed that compared to NEB, using MDI+S for the delivery of albuterol was associated with lower total costs (US$96.68 vs US$121.41 average cost per patient) and a higher probability of hospital admission avoided (0.9219 vs 0.8900), thus leading to dominance. CONCLUSIONS: This study shows that in Colombia, an MIC, compared with NEB, the use of MDI+S for delivering albuterol for the treatment of pediatric asthma exacerbations is the preferred strategy because it is associated with a lower probability of hospital admission at lower total treatment costs.

Forced expiratory volumes in 3 s is a sensitive clinical measure for assessment of bronchodilator reversibility in elderly Chinese with severe lung function impairment.

Purpose: Sensitively assessing bronchial reversibility by spirometry is difficult in patients with serious airflow limitation and the elderly. Some patients cannot exhale for ≥6 s to achieve FVC testing criteria. The aim of this study was to assess if FEV3 could be a more sensitive and an acceptable surrogate for evaluating bronchial reversibility in such patients. Patients and methods: Subjects who had undergone pulmonary function examination in Beijing hospital from July 2003 to April 2015 were included in the study. Patients with FEV1<50% of the predicted value were classified as the severely lung function-impaired group. Correlation between the severity of lung function impairment and changes in FEV1, FEV3 and FVC in response to a bronchodilator was estimated. Results: A total of 7745 tests on elderly subjects with a median age of 71 years were reviewed. The severely lung function-impaired group of 1728 accounted for 22.3% of the total number of subjects. There were significantly more patients in the severely lung function-impaired group who exhibited positive response in FEV3 or FVC and negative response in FEV1 after bronchodilator test (FEV1 negative response but FVC positive response, χ2=626.97, P<0.001; FEV1 negative response but FEV3 positive response, χ2=372.83, P<0.001). With the progressive increase in lung function impairment, ΔFEV1 increased and then declined, while ΔFVC and ΔFEV3 increased progressively. Changes in FEV3 or FVC significantly exceeded the change in FEV1 in the severely lung function-impaired groups (P<0.001). Conclusion: In elderly subjects, especially those with severe lung function impairment, FEV3 combined with FVC is a more effective and sensitive primary clinical outcome measure to detect bronchial reversibility. In subjects who cannot complete ≥6 s forced expiration and whose FVC is unreliable, FEV3 combined with FEV1 might be clinically more valuable in detecting bronchial reversibility.

Understanding medicines with a propensity to increase the risk of heart failure: Combining existing knowledge with targeted population assessment.

PURPOSE: Existing knowledge of medicines that increase the risk of an adverse event may be corroborated and augmented by population studies specifically assessing the risk associated with the concurrent use of these medicines and use by patients with existing comorbidity. An American Heart Association review recently identified a variety of medicines that may cause or exacerbate heart failure (HF), many with evidence from limited evaluation of population data. We assessed the risk of first-time HF associated with the use of 50 of these medicines by New Zealand's primary care population. METHODS: Case-control study utilising national pharmaceutical use and hospital admissions data 2007-2015; 22,989 patients with first-time HF 2008-2015 were matched with 114 498 control patients. The primary outcome was first-time HF and its association with medicine exposure in the prior 90 days, estimated using conditional logistic regression. We also assessed the risk associated with new use of medicines in the prior month, concurrent use, and in patients with existing comorbidity. RESULTS: Eleven medicines were significantly associated with HF with several other infrequently used medicines providing signals of increased risk. A high risk was associated with the use of salbutamol (adjusted odds ratio 2.63; 95% CI, 2.48-2.78), clozapine (2.70; 2.46-4.98), diltiazem (1.52; 1.44-1.60), indomethacin (2.51; 1.54-4.10), pioglitazone (1.50; 1.16-1.95), and antifungal medicines. New use of medicines and use of medicine combinations increased this risk in many cases. CONCLUSIONS: Our study provides further evidence to inform cautious use of these medicines in patients with HF or at risk of developing HF.

Assessment of Dry Powder Inhaler Carrier Targeted Design: A Comparative Case Study of Diverse Anomeric Compositions and Physical Properties of Lactose.

The pulmonary administration landscape has rapidly advanced in recent years. Targeted design of particles by spray-drying for dry powder inhaler development offers an invaluable tool for engineering of new carriers. In this work, different formulation and process aspects of spray-drying were exploited to produce new lactose carriers. Using an integrated approach, lactose was spray-dried in the presence of polyethylene glycol 200 (PEG 200), and the in vitro performance of the resulting particles was compared with other grades of lactose with varying anomeric compositions and/or physical properties. The anomeric composition of lactose in lactose-PEG 200 feed solutions of variable compositions was analyzed via polarimetry at different temperatures. These results were correlated with the solid-state and anomeric composition of the resulting spray-dried particles using modulated differential scanning calorimetry and wide-angle X-ray scattering. The distinct selected grades of lactose were characterized in terms of their micromeritic properties using laser diffraction, helium pycnometry, and gas adsorption, and their particle surface morphologies were evaluated via scanning electron microscopy. Adhesive mixtures of the different lactose carriers with inhalable-sized salbutamol sulfate, as a model drug, were prepared in low doses and evaluated for their blend homogeneity and aerodynamic performance using a Next Generation Impactor. Characterization of the spray-dried particles revealed that predominantly crystalline (in an anomeric ratio 0.8:1 of α to ß) spherical particles with a mean size of 50.9 ± 0.4 µm could be produced. Finally, it was apparent that micromeritic, in particular, the shape, and surface properties (inherent to solid-state and anomeric composition) of carrier particles dominantly control DPI delivery. This provided an insight into the relatively inferior performance of the adhesive blends containing the spherical spray-dried lactose-PEG 200 composites.

Beware of beta! A case of salbutamol-induced lactic acidosis in severe asthma.

A 22-year-old woman presented with symptoms and signs consistent with acute severe asthma. After significant doses of beta-agonist, she developed a significant lactic acidosis. Significant issues arose in this patient's history with regards to purchase of medications, compliance and follow-up with respiratory service. Beta-adrenergic receptors when stimulated have been hypothesised to increase lipolysis, producing free fatty acids, which inhibit the conversion of pyruvate to coenzyme A within the Krebs cycle. Additional pyruvate is generated through stimulation of glycolysis and glycogenolysis through simultaneous catecholamine surge. This increased pyruvate load is shunted through anaerobic glycolysis, producing increased lactate. Steroid use during an asthma attack enhances the beta-2 receptor sensitivity, further potentiating lactate production. The hyperadrenergic state in this young asthmatic likely resulted in pyruvate and therefore lactate rise and thus metabolic acidosis as mentioned before. This piece highlights a physiological phenomenon that may occur in the context of iatrogenic hyperadrenergism.

Investigation of a potential drug-drug interaction between salbutamol and ambroxol and bioequivalence of a new fixed-dose combination containing these two drugs in healthy Chinese subjects.

OBJECTIVES: The aims of the study were to investigate the potential drug-drug interaction between salbutamol and ambroxol, the bioequivalence of the new fixed-dose combination containing salbutamol and ambroxol compared with co-administration of the two separate formulations, and to describe the safety and tolerability of the fixed-dose combination formulation in healthy Chinese volunteers. MATERIALS AND METHODS: An open-label, single-dose, four-treatment, four-period crossover study for evaluation of drug-drug interaction and bioequivalence (n = 24) was performed. Each participant received salbutamol 4 mg, ambroxol 15 mg, salbutamol 4 mg co-administered with ambroxol 15 mg or fixed-dose combination formulation (salbutamol 4 mg and ambroxol 15 mg). Plasma concentrations of two analytes were determined with the use of validated LC-MS/MS method. Safety and tolerability were assessed by recording adverse events. RESULTS: Co-administration of salbutamol and ambroxol was not associated with a significant influence on single salbutamol or ambroxol pharmacokinetics. After statistical comparisons of log-transformed Cmax and AUC of salbutamol and ambroxol between fixed-dose combination and concomitant treatments, all 90% confidence intervals of geometric mean ratios were within the predefined equivalence range of 80 - 125%. No serious adverse events were reported, and all treatments were safe and well tolerated in Chinese healthy subjects. CONCLUSION: There were no significant drug-drug pharmacokinetic interactions between salbutamol and ambroxol after oral administration. The new formulation was bioequivalent to the co-administration of two drugs in separate dosage forms.
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Pediatric Anaphylaxis in the Prehospital Setting: Incidence, Characteristics, and Management.

OBJECTIVE: Although hospital presentations for pediatric anaphylaxis have been described in the literature, a minimal amount is known regarding the incidence, characteristics, and management of pediatric anaphylaxis presenting to emergency medical services (EMS). METHODS: We performed a retrospective observational study of pediatrics (≤16 years) presenting to EMS in Victoria, Australia. Patients with suspected anaphylaxis were included if they were treated with epinephrine before or after EMS arrival. We used descriptive statistics to compare baseline characteristics and linear regression to assess trends in incidence over time. RESULTS: Between July 2008 and June 2016, we identified 2,137 pediatric anaphylaxis presentations. Overall, 59% were male and 70% had pre-existing anaphylaxis. The age-adjusted incidence increased over the study period, from 11.8 presentations per 100,000 person-years in 2008-09 to 38.7 in 2015-16 (p for trend < 0.001). Common suspected allergens included nuts (52%) and dairy/milk formula (17%). In total, 1,333 (62%) patients received epinephrine via an autoinjector, and 51 (2%) from a doctor before EMS arrival. When compared to patients receiving epinephrine after EMS arrival, patients treated prior were more likely to present with vital signs within normal limits, including heart rate (66% vs. 84%, p < 0.001), systolic blood pressure (77% vs. 93%, p < 0.001) and respiratory rate (79% vs. 91%, p < 0.001). The most common EMS interventions were intramuscular epinephrine (45%) and inhaled salbutamol (14%). Three out-of-hospital cardiac arrests were observed, two of whom received endotracheal intubation. CONCLUSION: The incidence of prehospital pediatric anaphylaxis is increasing significantly. Despite this, most patients are hemodynamically stable on presentation and few require emergency treatments beyond the administration of intramuscular epinephrine.

Frequency of stepping down antibiotics and nebuliser treatment is lower at weekends compared to weekdays: an observational study.

We hypothesised that delays in providing non-urgent medication step-downs at weekends to medical management may be associated with increased length of stay.In a novel use of electronic prescribing data, we analysed emergency admissions from a busy acute medical hospital over 52 weeks from November 2014 to October 2015. The main outcomes of interest were switching from intravenous antibiotics to oral antibiotics and stopping nebulised bronchodilators. The rate of switching from intravenous to oral antibiotics was lower on Saturdays and Sundays compared with weekdays, and the rate of stopping nebulised bronchodilators was similarly lower at weekends (p<0.001). Median length of stay was shorter in those whose antibiotic treatment was stepped down at weekends compared with weekdays (4 days versus 5 days, p<0.001). Reduced medication step-downs at weekends may represent a bottleneck in patient flow. Electronic prescribing data are a valuable resource for future health services research.

Modeling Seasonal and Spatiotemporal Variation: The Example of Respiratory Prescribing.

Many measures of chronic diseases, including respiratory disease, exhibit seasonal variation together with residual correlation between consecutive time periods and neighboring areas. We demonstrate a strategy for modeling data that exhibit both seasonal trend and spatiotemporal correlation, using an application to respiratory prescribing. We analyzed 55 months (2002-2006) of prescribing data from the northeast of England, in the United Kingdom. We estimated the seasonal pattern of prescribing by fitting a dynamic harmonic regression (DHR) model to salbutamol prescribing in relation to temperature. We compared the output of DHR models to static sinusoidal regression models. We used the DHR-fitted values as an offset in mixed-effects models that aimed to account for the remaining spatiotemporal variation in prescribing rates. As diagnostic checks, we assessed spatial and temporal correlation separately and jointly. Our application of a DHR model resulted in a better fit to the seasonal variation of prescribing than was obtained with a static model. After adjusting for the fitted values from the DHR model, we did not detect any remaining spatiotemporal correlation in the model's residuals. Using a DHR model and temperature data to account for the periodicity of prescribing proved to be an efficient way to capture its seasonal variation. The diagnostic procedures indicated that there was no need to model any remaining correlation explicitly.

Multidisciplinary intervention to improve albuterol inhaler utilization among patients with asthma.

OBJECTIVE: The goal of this study was to examine the impact of a multidisciplinary intervention designed to improve appropriate albuterol inhaler utilization among patients with asthma. METHODS: This was a pre-post retrospective analysis. The study intervention included written information sent directly to patients, educated prescribers, and enhanced pharmacist training on appropriate albuterol inhaler utilization. Eligible study patients had a diagnosis of asthma and purchased at least two albuterol inhalers between 07/12/2012 and 06/30/2013 (pre-period) and 7/01/2013 to 06/30/2014 (post-period). The primary outcome was a comparison between study periods of the count of albuterol inhalers purchased per patient per month (PPPM). RESULTS: The median age of included patients was 41 years, 53% were females, and allergic rhinitis was the most common comorbidity. The median albuterol inhalers purchased PPPM decreased from 0.60 (interquartile range [IQR] = 0.39-0.87) to 0.37 (IQR = 0.26-0.53) from the pre- to post-period (p < 0.001). The proportion of patients with at least one systemic corticosteroid purchase decreased (36% vs. 31%) and >1 albuterol inhaler purchased on the same day increased (3.1% vs. 5.7%) from the pre- to post-period (p < 0.001). Numerically, the proportion of participants who experienced an acute asthma exacerbation decreased and asthma controller inhalers purchased PPPM increased but these did not reach statistical significance (both p > 0.05). CONCLUSIONS: A multidisciplinary approach to increasing appropriate albuterol inhaler use was associated with a decrease in albuterol inhalers purchased PPPM while not increasing acute asthma exacerbations. Future study is needed to evaluate patient perspectives on this intervention and assess its economic impact.

Clinical outcomes of levalbuterol versus racemic albuterol in pediatric patients with asthma: Propensity score matching approach in a medicaid population.

OBJECTIVE: Racemic albuterol and levalbuterol are used to treat acute episodes of asthma. The main objective of this study was to compare levalbuterol therapy to albuterol therapy on incidence rates of subsequent emergency department (ED) visits and hospitalizations. METHOD: We conducted a retrospective cohort study of asthmatic children who had pharmacy refills for levalbuterol/albuterol in the South Carolina Medicaid database in 2002-2011. Children receiving levalbuterol were matched to those receiving albuterol using propensity score matching technique. For ED visits and separately for hospitalizations, multivariable negative binomial regression was used to estimate the two group-specific incidence rates and the incidence rate ratio (IRR). RESULTS: A total of 8,172 asthmatic patients aged 2-18 years were identified in the South Carolina Medicaid database. During the 12-month follow-up period, the levalbuterol group had fewer asthma-related ED visits and hospitalizations: 939 (11.49%) children had asthma-related ED visits (levalbuterol: 8.76%; albuterol: 14.21%), and 89 (1.09%) children had asthma-related hospitalizations (levalbuterol: 1.07%; albuterol: 1.12%). Comparing the levalbuterol group to the albuterol group, the adjusted IRR estimate was 0.57 (95% confidence interval [CI], 0.49-0.65) for of asthma-related ED visits, and 0.93 (95%CI, 0.99-1.63) for hospitalizations. Children filling levalbuterol also had a lower IRR of all-cause ED visit (0.88; 95%CI, 0.82-0.95), but similar IRR of all-cause hospitalizations (1.08; 95%CI, 0.82-1.42). CONCLUSION: This observational study of children aged 2-18 demonstrated levalbuterol prescription fills were associated with reduced ED visits, but not hospitalizations. Additional research may be necessary to assess this association. Pediatr Pulmonol. 2017;52:516-523. © 2016 Wiley Periodicals, Inc.

A Cost Analysis of Salbutamol Administration by Metered-Dose Inhalers with Spacers versus Nebulization for Patients with Wheeze in the Pediatric Emergency Department: Evidence from Observational Data in Nova Scotia.

BACKGROUND: Despite evidence demonstrating the advantages of metered-dose inhalers with spacers (MDI-s), nebulization (NEB) remains the primary method of asthma treatment in some pediatric emergency departments (PEDs). There is a perception that delivering salbutamol by MDI-s is more costly than by NEB. This research evaluates the relative costs of MDI-s and NEB using local, hospital-specific, patient-level data. METHODS: Regression models estimated associations between the salbutamol inhalation method and costs, length of stay (LOS) in the PED and hospital, and the probability of admission. Our population was a random sample of 822 patients presenting with wheeze to the PED in 2008/2009. Control variables included age, sex, triage acuity, time of PED visit, other medications, and vitals. Costs were calculated using the prices and quantities of medical resources used per treatment. Probabilistic sensitivity analysis was used. RESULTS: Treatment with MDI-s versus NEB was associated with an absolute decrease in hospitalization of 4.4% (p<0.05) and a 25-hour (p<0.001) reduction in average inpatient stay, after controlling for triage acuity and patient characteristics. This resulted in savings of $24/patient in the PED and $180/patient overall (p<0.001). Inpatient care accounted for more than 90% of total patient costs. CONCLUSIONS: Our results suggest economic gains associated with MDI-s for salbutamol inhalation in PEDs. Sensitivity analyses show that this conclusion is not affected by changes in model parameters that may differ by jurisdiction. Since most facilities already collect the data used for this study, our methods could be adopted for a cross-jurisdictional account of the cost effectiveness of MDI-s.

Use of a Shared Canister Protocol for the Delivery of Metered-Dose Inhalers in Mechanically Ventilated Subjects.

BACKGROUND: Mechanically ventilated patients often need bronchodilators administered via a metered-dose inhaler (MDI). Unfortunately, there are no data examining the impact of shared canister delivery of MDI therapy in mechanically ventilated patients. METHODS: A prospective trial was conducted with subjects assigned to shared canister MDI therapy or single-patient canister MDI therapy. Outcomes assessed were occurrence of ventilator-associated pneumonia (VAP), hospital mortality, length of stay, ventilator-associated events, and MDI costs. RESULTS: Among 486 screened patients, 353 were included for analysis of which 201 (56.9%) received shared canister MDI therapy and 152 (43.1%) received single-patient canister therapy. VAP (7.0% vs 4.6%, P = .35), hospital mortality (21.9% vs 20.4%, P = .73), and ventilator days (median [interquartile range] 3.1 [0.9-7.5] d vs 2.7 [1.2-7.1] d, P = .62) were similar between the shared canister and single-patient canister groups. We did not observe clinically important differences for ventilator-associated events between study groups in our logistic regression analysis (P = .07). There was a savings of $217/subject in the shared canister group due to the use of 299 fewer MDIs. CONCLUSIONS: Our study found that shared canister MDI therapy compared with single-patient MDI use was associated with a significant cost savings and similar rates of VAP, hospital mortality, and length of stay but a greater prevalence of ventilator-associated events. This finding suggests that shared canister delivery of MDIs may be a cost-effective practice in mechanically ventilated patients. Based on our findings, further studies examining the overall safety of shared canister use in mechanically ventilated patients seem warranted before recommending their routine use. (ClinicalTrials.gov registration NCT01935388.).

Financial effect of converting ipratropium-albuterol therapy from inhalers to nebulizer treatments at an academic health system.

PURPOSE: The results of a study to assess the financial impact of an automatic formulary substitution of ipratropium-albuterol nebulization solution for ipratropium-albuterol metered-dose inhalers (MDIs) at an academic health system are reported. METHODS: The study was conducted at a 1242-bed urban academic health system. Data were collected regarding all respiratory medication administrations during a three-month period before the MDI-to-nebulizer substitution (October-December 2012) and the same period of 2013 (after the substitution was implemented). Purchasing data were compared between the two time periods to measure the impact of the formulary substitution on pharmacy department costs, and documented administrations were assessed to evaluate associated changes in respiratory therapist (RT) workload. RESULTS: With 100% prescriber compliance with the formulary substitution, the number of MDI administrations of ipratropium-albuterol declined from 13,667 in October-December 2012 to zero in the same period of 2013. The substitution required expenditures for equipment (vibrating mesh nebulizer technology and patient-specific kits) and RT personnel (one additional RT was hired), but those added costs were substantially outweighed by cost savings resulting from a substantial reduction in overall respiratory drug spending. CONCLUSION: An automatic substitution of ipratropium-albuterol nebulization solution for MDIs resulted in a three-month savings of $99,359 in drug cost and an extrapolated full-year savings of $397,436. When additional costs associated with the substitution were taken into account, there was an overall savings of $146,806 during the implementation year and a projected savings of $257,936 for each following year.

Medical and pharmacological approach to adjust the salbutamol anti-doping policy in athletes.

BACKGROUND: Salbutamol abuse detection by athletes is based on a urinary upper threshold defined by the World Anti-Doping Agency (WADA). However, this threshold was determined in healthy, untrained individuals and after a dose of salbutamol inhaled that might not really mirror the condition of asthmatic athletes and the experts's guidelines for asthma management. We aimed to revise this threshold in accordance with recommended clinical practice (that appear to be different from the actual WADA recommendation) and in exercise conditions. METHODS: For the present open-label design study, we included 12 trained male cyclists (20 to 40 y/o) with asthma. Differently from the previous pharmacokinetic study supporting the actual salbutamol urinary upper threshold, we decided to administer a close to recommended clinical practice daily dose of 3x200 µg.d(-1) inhaled salbutamol (instead of 1600 µg.d(-1) as authorized by the anti-doping policy). Urine salbutamol concentration was quantified by liquid chromatography-tandem ion trap mass spectrometry and corrected for urine density, at rest and after a 90-min cycling effort at 70-80 % of the maximal aerobic power. RESULTS: The maximum urine salbutamol concentration value peaked after the cycling effort and was 510 ng.mL(-1). That is twice lower than the actual WADA threshold to sanction salbutamol abuse, this "legal" threshold being based on pharmacokinetic data after a daily dose that is 8 fold the total dose sequentially administrated in our study. Considering its 95 % confidence interval, this threshold value could be more stringent. CONCLUSION: By using conditions in accordance with the experts' clinical and safety guidelines for asthma management in athletes undergoing an intense exercise bout, our study suggests that the urine salbutamol concentration threshold could be lowered to redefine the rule supporting the decision to sanction an athlete for salbutamol abuse.

Preventive nebulization of mucolytic agents and bronchodilating drugs in invasively ventilated intensive care unit patients (NEBULAE): study protocol for a randomized controlled trial.

BACKGROUND: Preventive nebulization of mucolytic agents and bronchodilating drugs is a strategy aimed at the prevention of sputum plugging, and therefore atelectasis and pneumonia, in intubated and ventilated intensive care unit (ICU) patients. The present trial aims to compare a strategy using the preventive nebulization of acetylcysteine and salbutamol with nebulization on indication in intubated and ventilated ICU patients. METHODS/DESIGN: The preventive nebulization of mucolytic agents and bronchodilating drugs in invasively ventilated intensive care unit patients (NEBULAE) trial is a national multicenter open-label, two-armed, randomized controlled non-inferiority trial in the Netherlands. Nine hundred and fifty intubated and ventilated ICU patients with an anticipated duration of invasive ventilation of more than 24 hours will be randomly assigned to receive either a strategy consisting of preventive nebulization of acetylcysteine and salbutamol or a strategy consisting of nebulization of acetylcysteine and/or salbutamol on indication. The primary endpoint is the number of ventilator-free days and surviving on day 28. Secondary endpoints include ICU and hospital length of stay, ICU and hospital mortality, the occurrence of predefined pulmonary complications (acute respiratory distress syndrome, pneumonia, large atelectasis and pneumothorax), and the occurrence of predefined side effects of the intervention. Related healthcare costs will be estimated in a cost-benefit and budget-impact analysis. DISCUSSION: The NEBULAE trial is the first randomized controlled trial powered to investigate whether preventive nebulization of acetylcysteine and salbutamol shortens the duration of ventilation in critically ill patients. TRIAL REGISTRATION: NCT02159196, registered on 6 June 2014.

The Impact of the US Food and Drug Administration Chlorofluorocarbon Ban on Out-of-pocket Costs and Use of Albuterol Inhalers Among Individuals With Asthma.

IMPORTANCE: The US Clean Air Act prohibits use of nonessential ozone-depleting substances. In 2005, the US Food and Drug Administration announced the ban of chlorofluorocarbon (CFC) albuterol inhalers by December 31, 2008. The policy resulted in the controversial replacement of generic CFC inhalers by more expensive, branded hydrofluoroalkane inhalers. The policy's impact on out-of-pocket costs and utilization of albuterol is unknown. OBJECTIVE: To study the impact of the US Food and Drug Administration's CFC ban on out-of-pocket costs and utilization of albuterol inhalers. DESIGN, SETTING, AND PARTICIPANTS: Using private insurance data from January 1, 2004, to December 31, 2010, we investigated the effect of the CFC ban on out-of-pocket costs and utilization of albuterol inhalers among individuals with asthma (109,428 adults; 37,281 children), as well as asthma-related hospitalizations, emergency department visits, and outpatient visits. We estimated multivariable models adjusted for age, sex, comorbidities, and mean out-of-pocket costs of albuterol inhalers in an individual's drug plan. We analyzed whether effects varied between adults vs children and those with persistent vs nonpersistent asthma. MAIN OUTCOMES AND MEASURES: Pharmacy claims for albuterol inhalers, as well as asthma-related hospitalizations, emergency department visits, and outpatient visits. RESULTS: The mean out-of-pocket albuterol cost rose from $13.60 (95% CI, $13.40-$13.70) per prescription in 2004 to $25.00 (95% CI, $24.80-$25.20) immediately after the 2008 ban. By the end of 2010, costs had lowered to $21.00 (95% CI, $20.80-$21.20) per prescription. Overall albuterol inhaler use steadily declined from 2004 to 2010. Steep declines in use of generic CFC inhalers occurred after the fourth quarter of 2006 and were almost fully offset by increases in use of hydrofluoroalkane inhalers. In multivariable analyses, a $10 increase in out-of-pocket albuterol prescription costs was estimated to lower utilization by 0.92 percentage points (95% CI, -1.39 to -0.44; P < .001) for adults and 0.54 percentage points (95% CI, -0.84 to -0.24; P = .001) for children, with no difference between adults vs children and patients with persistent vs nonpersistent asthma and with no impact on asthma-related hospitalizations, emergency department visits, and outpatient visits. CONCLUSIONS AND RELEVANCE: The Federal ban of CFC inhalers led to large relative increases in out-of-pocket albuterol costs among privately insured individuals with asthma and modest declines in utilization. The policy's impact on individuals without insurance, who faced greater cost increases, is unknown.

COST-effectiveness of salmeterol/fluticasone propionate combination (Advair(®)) in uncontrolled asthma in Canada.

OBJECTIVE: To evaluate the cost-utility of the treatment with a long acting beta-agonist (LABA) and inhaled corticosteroid (ICS) combination inhaler [salmeterol xinafoate (SAL)/fluticasone propionate (FP) combination inhaler (SFC) (Advair(®))] to continuing on current ICS dose (no ICS dose change) or increased ICS dose [fluticasone propionate (FP)] in patients with uncontrolled asthma in Canada. METHODS: A cost-utility analysis was conducted from a Canadian public healthcare perspective with a one year time horizon. In the no FP dose change scenarios, remaining on daily low (FP 100 ug BID) or medium (FP 200-250 ug BID) or high dose (FP 500 ug BID) was considered. In the increased FP dose scenarios, doubling the FP dose from low to medium dose and from medium to high dose regimens were considered. A decision model was developed with two health states: "symptom free" or "with symptoms". Clinical efficacy was based on a meta-analysis of relevant randomized controlled trials. Over the one year time horizon the percentage with symptom free days (SFD) was used as the measure of differential treatment scenario effectiveness. Drug costs and non-drug costs were incorporated into the analysis. Utilities, derived from EQ5D scores and health services resource use based on patient diaries for 'symptom free' and 'with symptoms' were based on regression analyses of individual patient data from the Gaining Optimal Asthma controL (GOAL) trial. Costs were assessed by assigning unit cost for each health services resource use for each patient. The incremental cost-utility ratios (ICUR) for SFC vs no FP dose change or increased FP dose were estimated using descriptive statistics. Uncertainty was assessed by deterministic and probabilistic sensitivity analysis (PSA). RESULTS: Over one year, SFC resulted in an incremental cost per patient of $544-$655 compared to no FP dose change and $47-$380 per year compared to increased FP dose. SFC results in incremental QALYs per patient of 0.0100-0.0149 compared to no FP dose change and 0.0136-0.0152 compared to increased FP dose. The one year ICURs were $43,000 to $54,400 per QALY gained for SFC compared to no FP dose change and $25,000 to $3500 per QALY gained compared to increased FP dose scenarios. The probability of SFC being cost-effective at $50,000 per QALY gained was greater than 75% compared to increased FP dose scenarios and compared to no dose change for patients on low or medium dose FP. The results were robust to changes in assumptions within the model. CONCLUSION: In Canadian patients with inadequately controlled asthma on FP, it is cost-effective to use SFC for patients 12 years and over compared to doubling their FP dose. It is also cost-effective to use SFC for patients on low or medium dose FP compared to remaining on the current FP dose in patients with uncontrolled asthma.

A simple rule to identify patients with chronic obstructive pulmonary disease who may need treatment reevaluation.

BACKGROUND: A simple rule based on short-acting inhaled ß2-agonist (SABA) use could identify patients with chronic obstructive pulmonary disease (COPD) at increased risk of exacerbations and signal the need for maintenance therapy change, similar to asthma "Rules of Two(®)". METHODS: Associations between SABA use, COPD exacerbations, and health care costs over 1 year were examined retrospectively using de-identified patient data from the Optum Research Database (ORD; N = 56,581) and the Impact National Benchmark Database (IMPACT™; N = 9423). Nebulized and metered-dose inhaler (MDI) SABA doses were normalized to 2.5 mg and 90 mcg albuterol equivalents, respectively. RESULTS: The GOLD initiative establishes ≥2 exacerbations/year as indicative of increased risk in COPD. We identified a correlation (p < 0.0001) between 1.5 SABA doses/day and this frequency of exacerbations. In ORD, patients using ≥1.5 versus <1.5 SABA doses/day experienced significantly more exacerbations: 1.92 (95% confidence interval [CI], 1.89-1.96) versus 1.36 (95% CI, 1.34-1.38) per patient year (PPY). Above-threshold use was associated with higher average annual COPD-related costs (2010 $US): $21,868 (standard deviation [SD], $53,910) versus $11,686 (SD, $32,707) for nebulized SABA only, $9216 (SD, $30,710) versus $7334 (SD, $24,853) for MDI SABA only, and $15,806 (SD, $35,260) versus $11,233 (SD, $27,006) for both nebulized and MDI SABA. IMPACT™ validated these findings. CONCLUSION: Patients with COPD using ≥1.5 SABA doses/day were at increased risk of exacerbations. Our results suggest a "Rule of 3-2": SABA use ≥3 times in 2 days should be considered a clinical marker for needing treatment reevaluation.