Asthma severity categorization using a claims-based algorithm or pulmonary function testing.

OBJECTIVES: This study was performed to determine whether pulmonary function test results would appreciably alter asthma severity categorization determined by an algorithm using information readily available in administrative databases. METHODS: Patients 6 to 64 years of age with asthma diagnosed from 1999-2005, who had at least one pulmonary function test, were identified from a claims database of a medical group practice located in central Massachusetts. Asthma severity for these patients was categorized using information available in an administrative database (claims-based algorithm) and by percent predicted forced expiratory volume in 1 second (FEV(1)) or peak expiratory flow (PEF) abstracted from medical charts (pulmonary function test method). Gamma rank correlation index was used to measure the association between the two severity categorization methods. Total and asthma-related healthcare costs for each severity category were compared between the two different approaches. RESULTS: There was a significant ordinal association between severity categorization with the two classification approaches (p = 0.0002). The pulmonary function test method resulted in more frequent mild categorizations and less frequent moderate and severe categorizations than the claims-based algorithm. In only 10.9% of patients did the pulmonary function test method result in a more severe asthma category than the claims-based algorithm. Patients with more severe asthma, determined by both methods, had higher total and asthma-related health care costs. Total and asthma-related health care costs were similar for each asthma severity categorization for the two classification approaches, except for asthma-related costs in the moderate severity categories. CONCLUSION: The claims-based algorithm generally categorized patients as having more severe asthma than the approach using pulmonary function test results. Pulmonary function test results would have appreciably changed asthma severity categorization in only a small percent of patients. These findings add further support to the use of administrative database analyses for the evaluation of asthma care in large populations.

Economic burden of pneumonia in an employed population.

OBJECTIVE: To estimate the overall economic burden of pneumonia from an employer perspective. METHODS: The annual, per capita cost of pneumonia was determined for beneficiaries of a major employer by analyzing medical, pharmaceutical, and disability claims data. The incremental costs of 4036 patients with a diagnosis of pneumonia identified in a health claims database of a national Fortune 100 company were compared with a 10% random sample of beneficiaries in the employer overall population. RESULTS: Total annual, per capita, employer costs were approximately 5 times higher for patients with pneumonia ($11 544) than among typical beneficiaries in the employer overall population ($2368). The increases in costs were for all components (eg, medical care, prescription drug, disability, and particularly for inpatient services). A small proportion (10%) of pneumonia patients (almost all of whom were hospitalized) accounted for most (59%) of the costs. CONCLUSIONS: Patients with pneumonia present an important financial burden to employers. These patients use more medical care services, particularly inpatient services, than the average beneficiary in the employer overall population. In addition to direct health care costs related to medical utilization and the use of prescription drugs, indirect costs due to disability and absenteeism also contribute to the high cost of pneumonia to an employer.

Impact of noninvasive studies to distinguish volume overload from ARDS in acutely ill patients with pulmonary edema: analysis of the medical literature from 1966 to 1998.

STUDY OBJECTIVE: To assess the impact of substituting noninvasive diagnostic studies for Swan-Ganz catheter (SGC) placement in the evaluation of acutely ill patients. DESIGN: Modified decision analysis. METHODS: Using published studies that define effectiveness of clinical examination, echocardiography, and SGC placement to diagnose pulmonary edema, an analysis of the impact of substituting three diagnostic approaches using (1) clinical assessment (CA), (2) M-mode two-dimensional transthoracic echocardiography (EC), or (3) CA then EC if necessary for SGC placement was considered. STUDY POPULATION: Patients with acute respiratory distress and radiographic findings of pulmonary edema, and ICU patients with hypotension and/or pulmonary edema without acute cardiac ischemia. INTERVENTIONS: Three approaches using noninvasive studies were substituted for placement of SGC in the initial evaluation of pulmonary edema. MEASUREMENTS AND RESULTS: The number of SGCs placed, the number of tests needed to diagnose (NTND) all cases of volume overload, and the total number of procedure-related adverse events were calculated for each diagnostic approach and compared to SGC placement. EC, and CA then EC approaches produced fewer procedure-related serious complications and deaths, compared to the SGC approach; however, these approaches also produced a higher NTND and total procedures performed than did the SGC or CA approaches. The CA approach led to reduced NTND and procedure-related adverse events. CONCLUSIONS: Substituting noninvasive studies for SGC placement in the initial evaluation of acutely ill patients may slightly reduce procedure-related adverse events, but it may also increase the number of procedures performed. Studies of SGC use are warranted and need to include a clinical assessment control group and an analysis of resource utilization.

Medical and surgical treatment of parapneumonic effusions : an evidence-based guideline.

OBJECTIVE: A panel was convened by the Health and Science Policy Committee of the American College of Chest Physicians to develop a clinical practice guideline on the medical and surgical treatment of parapneumonic effusions (PPE) using evidence-based methods. OPTIONS AND OUTCOMES CONSIDERED: Based on consensus of clinical opinion, the expert panel developed an annotated table for evaluating the risk for poor outcome in patients with PPE. Estimates of the risk for poor outcome were based on the clinical judgment that, without adequate drainage of the pleural space, the patient with PPE would be likely to have any or all of the following: prolonged hospitalization, prolonged evidence of systemic toxicity, increased morbidity from any drainage procedure, increased risk for residual ventilatory impairment, increased risk for local spread of the inflammatory reaction, and increased mortality. Three variables, pleural space anatomy, pleural fluid bacteriology, and pleural fluid chemistry, were used in this annotated table to categorize patients into four separate risk levels for poor outcome: categories 1 (very low risk), 2 (low risk), 3 (moderate risk), and 4 (high risk). The panel's consensus opinion supported drainage for patients with moderate (category 3) or high (category 4) risk for a poor outcome, but not for patients with very low (category 1) or low (category 2) risk for a poor outcome. The medical literature was reviewed to evaluate the effectiveness of medical and surgical management approaches for patients with PPE at moderate or high risk for poor outcome. The panel grouped PPE management approaches into six categories: no drainage performed, therapeutic thoracentesis, tube thoracostomy, fibrinolytics, video-assisted thoracoscopic surgery (VATS), and surgery (including thoracotoiny with or without decortication and rib resection). The fibrinolytic approach required tube thoracostomy for administration of drug, and VATS included post-procedure tube thoracostomy. Surgery may have included concomitant lung resection and always included postoperative tube thoracostomy. All management approaches included appropriate treatment of the underlying pneumonia, including systemic antibiotics. Criteria for including articles in the panel review were adequate data provided for >/=20 adult patients with PPE to allow evaluation of at least one relevant outcome (death or need for a second intervention to manage the PPE); reasonable assurance provided that drainage was clinically appropriate (patients receiving drainage were either category 3 or category 4) and drainage procedure was adequately described; and original data were presented. The strength of panel recommendations on management of PPE was based on the following approach: level A, randomized, controlled trials with consistent results or individual randomized, controlled trial with narrow confidence interval (CI); level B, controlled cohort and case control series; level C, historically controlled series and case series; and level D, expert opinion without explicit critical appraisal or based on physiology, bench research, or "first principles." EVIDENCE: The literature review revealed 24 articles eligible for full review by the panel, 19 of which dealt with the primary management approach to PPE and 5 with a rescue approach after a previous approach had failed. Of the 19 involving the primary management approach to PPE, there were 3 randomized, controlled trials, 2 historically controlled series, and 14 case series. The number of patients included in the randomized controlled trials was small; methodologic weaknesses were found in the 19 articles describing the results of primary management approaches to PPE. The proportion and 95% CI of patients suffering each of the two relevant outcomes (death and need for a second intervention to manage the PPE) were calculated for the pooled data for each management approach from the 19 articles on the primary management approach. (ABST

Comparing inhaled corticosteroids.

There are currently available 5 different inhaled corticosteroids, in a variety of different inhalation delivery devices. In the near future there will certainly be more inhaled corticosteroids in newer inhalation delivery devices available in the United States. Tremendous amounts of information will be made available about the relative advantages and disadvantages of these new products. Most of this information will relate to measures of potency, pharmacokinetic profiles, and technical issues about the ease of use. The respiratory care practitioner should be aware that estimating the clinical benefits from the topical anti-inflammatory effects of these newer products will be difficult to determine from this information. Also difficult to understand will be the effects of easier to use inhalation delivery devices on patient adherence to prescribed inhaled corticosteroid dosing regimens. Information from well designed clinical trials should be the basis for comparing presently available and newly developed inhaled corticosteroids.

Comparable bronchodilation with hydrofluoroalkane-134a (HFA) albuterol and chlorofluorocarbons-11/12 (CFC) albuterol in children with asthma.

This was an open-label, parallel group, randomized, age-stratified, multicenter study designed to compare the safety and efficacy of regular use of albuterol formulated in hydrofluoroalkane-134a (HFA albuterol) and albuterol formulated in chlorofluorocarbons-11/12 (CFC albuterol) in children with asthma. Children age 4-11 years using a short-acting inhaled beta2-agonist for 6 months to manage stable asthma, and with a prestudy forced expiratory volume in 1 sec (FEV1) of >50% predicted after withholding short-acting inhaled beta2-agonists for at least 6 hr, an increase in FEV1 > or = 12% within 30 min after two puffs of CFC albuterol, and the capability to comply with medication withholding requirements were eligible for study entry. After screening evaluation, patients entered a minimum 7-day run-in period. On study day 1 spirometry and a baseline 12-lead electrocardiogram (ECG) were performed, pulse and blood pressure were measured, and patients self-administered two puffs of their randomized study drug, either HFA albuterol or CFC albuterol. Serial spirometry was performed over 6 hr after study drug dosing. Pulse and blood pressure were measured just prior to each spirometry and a 12-lead ECG was performed at 60 min postdose. Patients took two puffs of their study drug four times a day for 4 weeks. At study week 4, study day 1 procedures were repeated. Patients maintained a daily diary of morning (A.M.) and evening (P.M.) peak expiratory flow (PEF), daytime asthma symptom scores, nighttime asthma sleep disturbance scores, and study drug use. Demographics and baseline characteristics of the 63 patients randomized to HFA albuterol (33) and CFC albuterol (30) were similar. No significant differences were found between the HFA albuterol and CFC albuterol treatment groups for any of the primary or secondary FEV1 efficacy variables either at study day 1 or study week 4. No significant differences were noted between treatment groups for A.M. and P.M. PEF, individual asthma symptom scores, nighttime asthma sleep disturbance scores, and rescue study drug use over the 4-week study. No significant differences were found between the two treatment groups for change from predose in heart rate, systolic and diastolic blood pressure, and 12-lead ECG intervals at either study day 1 or study week 4. Adverse event reporting was similar for the two treatment groups. In this study, with regular use of HFA albuterol in children with asthma, there was a similar safety profile and comparable bronchodilator efficacy as with CFC albuterol.

Comparative effects of hydrofluoroalkane and chlorofluorocarbon beclomethasone dipropionate inhalation on small airways: assessment with functional helical thin-section computed tomography.

A double-blind, randomized, parallel-group pilot study compared the relative efficacy of hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP [QVAR]; mass median aerodynamic diameter, 0. 8-1.2 m) versus cholorofluorocarbon-11/12 BDP (CFC-BDP [Beclovent]; mass median aerodynamic diameter, 3.5-4.0 m) in 31 steroid naive patients with mild to moderate asthma (PC(20,) 4 mg/mL). Functional high-resolution computed tomography was used to assess the relative efficacy of HFA-BDP and CFC-BDP on regional air trapping, as an indirect measure of small airways function and on regional hyperreactivity. Pretreatment functional computed tomography was performed at residual volume before and after methacholine challenge. After 4 weeks of treatment, functional imaging was repeated before and after the same concentration of methacholine that was administered before the treatment (n = 19 patients). Quantitative assessment of changes in distribution of lung attenuation was performed. After 4 weeks of treatment, the HFA-BDP group showed significantly more improvement in air trapping overall (a shift in the lung attenuation curve at residual volume toward more attenuation) on the posttreatment computed tomography scan (P <.05; Fisher's Exact Test). After an equal constrictor stimulus (methacholine concentration), subjects treated with HFA-BDP (n = 10 patients) showed less increase in air trapping overall than subjects treated with CFC-BDP (n = 9 patients) on the posttreatment scans compared with the pretreatment scans (P <.001; Fisher's Exact Test). No significant difference was demonstrated between the 2 treatment groups with respect to improvement in symptoms, spirometry, or methacholine responsiveness assessed by FEV(1), except for a greater reduction in breathlessness in the HFA-BDP group (P <.05). We conclude that HFA-BDP may have greater efficacy in the peripheral airways and that this effect is better assessed with functional imaging computed tomography techniques than with conventional physiologic tests.

Efficacy response of inhaled beclomethasone dipropionate in asthma is proportional to dose and is improved by formulation with a new propellant.

BACKGROUND: This study tested the hypothesis that there would be improved asthma control with increasing doses of beclomethasone dipropionate (BDP) formulated in hydrofluoroalkane-134a (HFA-BDP) and the standard chlorofluorocarbon propellants (CFC-BDP). Because HFA-BDP has improved lung deposition compared with CFC-BDP, this study also tested the hypothesis that HFA-BDP would provide more effective control of asthma than CFC-BDP. METHODS: In this multicenter, randomized, parallel-group blinded study, asthmatic subjects who had deterioration in asthma control after discontinuation of inhaled corticosteroids were randomized to receive one of 6 possible treatments: 100 microg/d, 400 microg/d, or 800 microg/d of HFA-BDP or 100 microg/d, 400 microg/d, or 800 microg/d of CFC-BDP for 6 weeks. Changes in spirometry, daytime asthma symptom and nighttime asthma-related sleep disturbance scores, morning and evening peak expiratory flows, and daily use of inhaled beta-agonist for symptom control on diary cards were assessed over 6 weeks of treatment. RESULTS: Three hundred twenty-three patients were randomized to the 6 treatment groups, which had similar demographics and baseline lung function. There were significantly larger changes from baseline at week 6 in FEV(1) percent predicted with increasing doses of both HFA-BDP and CFC-BDP. The FEV(1) percent predicted dose-response curve for HFA-BDP was shifted to the left compared with the dose-response curve for CFC-BDP. By using the Finney bioassay method, it was calculated that 2.6 times as much CFC-BDP would be required to achieve the same improvement in FEV(1) percent predicted as HFA-BDP (95% confidence interval, 1.1-11.6). All treatment groups except the 100 microg/d CFC-BDP group tolerated study drug well. Ten (17%) of 59 patients in this group reported an acute asthma episode, increased asthma symptoms (6 of the 8 reports of increased asthma symptoms were classified as severe), or both, and 8 patients withdrew from the study (3 for adverse events related to asthma). CONCLUSIONS: Increasing doses of inhaled corticosteroids lead to improved lung function and asthma control. Moreover, the reformulation of BDP in HFA enables effective asthma control at much lower doses than CFC-BDP.

Proventil HFA prevents exercise-induced bronchoconstriction in children.

Short-acting inhaled beta2-agonists used just prior to exercise are an effective method for preventing exercise-induced bronchoconstriction (EIB) in children. This was a randomized, single-blind, placebo-controlled, four-period crossover study that compared the effectiveness of albuterol formulated in hydrofluoroalkane-134a (HFA) to albuterol formulated in chlorofluorocarbons (CFCs) and to placebo in protecting asthmatic children age 6-11 from EIB. Patients self-administered either HFA albuterol, two different CFC albuterol products, or placebo 30 min prior to exercise challenge. Spirometry was performed predose and 5, 10, 15, 30, 45, 60, 75, and 90 min after the exercise challenge was completed. The smallest percent change from the predose forced expiratory volume in 1 sec (FEV1) after exercise challenge was similar for the three active treatments, and each of the active treatments was significantly better than placebo. Each active treatment had significantly fewer patients unprotected from EIB (unprotected defined as having >20% fall in FEV1 after exercise challenge) than placebo. Changes in heart rate, blood pressure and electrocardiogram (ECG) intervals were similar for the three active treatments following exercise. HFA albuterol is as effective as albuterol products formulated in CFCs and more effective than placebo in protecting asthmatic children from EIB.

Categorizing asthma severity.

The National Asthma Education and Prevention Program (NAEPP) Expert Panel II recommended a stepped care pharmacotherapy approach to asthma treatment based on an objective assessment of asthma severity using daytime symptoms, nocturnal symptoms, and physiologic lung function. The worst grade of the individual variables determines overall asthma severity. With this approach, patterns of asthma severity categorization might vary among individual variables; one variable might have a predominant effect on overall categorization. During the run-in, pretreatment phase of five controlled clinical trials, data from 744 inhaled steroid nonusers and 685 inhaled steroid users on asthma control were collected and asthma severity categorized. In inhaled steroid nonusers nocturnal symptoms classified the majority of patients as severe, persistent, but wheeze classified 27.3% of patients as mild, intermittent and 25.7% as mild, persistent. If the worst grade from the four asthma symptoms was used for severity grading, most patients were categorized as severe, persistent. beta-Agonist use and FEV(1) classified most as moderate, persistent. There was poor correlation between variables in severity categorization. Severity grading for European patients was similar to that for U.S. patients. Applying the Expert Panel II recommended method for asthma severity categorization to a large data set illustrates that a single variable, nocturnal symptoms, determined to a large extent overall categorization. Development of a validated method for asthma severity categorization is essential for using a stepped care approach to asthma pharmacotherapy.

Practical management of pleural effusions. When and how should fluid accumulations be drained?

Management of pleural effusions requires recognition of the cause and initiation of disease-specific therapy. However, it is important to be forewarned that breathing problems do not always improve in these patients, since other disease processes may be contributing to dyspnea. Many options are available for draining effusions and preventing recurrence, but decisions often need to be made quickly so the process does not progress to the point at which intervention becomes much more difficult.

Evaluating pleural effusions. How should you go about finding the cause?

Although many pulmonary and systemic diseases are known to cause pleural effusions, analysis of the pleural fluid pinpoints the cause in most cases. Distinguishing pleural transudates from exudates is an important step. Transudate effusions are caused by a small, well-defined group of illnesses (e.g., cirrhosis, congestive heart failure). Exudative effusions, on the other hand, are associated with a wide variety of causes, including pneumonia, malignancy, TB, drug-induced reactions, and many others. Some effusions remain unexplained despite extensive tests. Surgical approaches may be appropriate for some of these patients, but the risks must be carefully weighed against the benefits.

Adrenal effects and pharmacokinetics of CFC-free beclomethasone dipropionate: a 14-day dose-response study.

Since equivalent efficacy is achieved with lower doses of the reformulated beclomethasone dipropionate in the chlorofluorocarbon (CFC)-free propellant HFA-134a (HFA) than with the original CFC-beclomethasone dipropionate formulation, it is possible the HFA-beclomethasone dipropionate may have less safety concerns than the CFC formulation. Despite its chronic use, the steady-state pharmacokinetics of beclomethasone dipropionate has never been studied before. This double-blind study examined adrenal effects and pharmacokinetics after 14 days of dosing with HFA-beclomethasone dipropionate. Forty-three steroid-naïve asthmatic patients were randomised into 5 parallel groups and dosed every 12 h for 14 days with: HFA-placebo; 200, 400 or 800 microg day(-1) HFA-beclomethasone dipropionate; or 800 microg day(-1) CFC-beclomethasone dipropionate. After two weeks of dosing, the 24-h urinary free cortisol of all but one patient remained within the normal range, showing that all doses were well tolerated from a systemic safety perspective. The active HFA-beclomethasone dipropionate treatment groups showed a dose-related fall in 24-h urinary free cortisol. Total-beclomethasone (beclomethasone dipropionate and metabolites) pharmacokinetics after either the first dose of HFA-beclomethasone dipropionate or CFC-beclomethasone dipropionate were not substantially affected by subsequent doses. The extent of drug absorption from 800 microg day(-1) HFA-beclomethasone dipropionate and CFC-beclomethasone dipropionate was in the ratio of 1.7 : 1. A non-linear correlation between 24-h urinary free cortisol and the pharmacokinetic parameters was observed, reflecting smaller changes in 24-h urinary free cortisol than in pharmacokinetics as the dose was increased. No clinically meaningful change in the pharmacokinetics of beclomethasone dipropionate plus metabolites was seen on multiple dosing. The greater systemic availability of HFA-beclomethasone dipropionate was still associated with adrenal effects comparable with that of the CFC formulation at the same dose.

Safety of long-term treatment with HFA albuterol.

BACKGROUND: Chlorofluorocarbons (CFCs) used as propellants in metered-dose inhalers deplete stratospheric ozone, which results in serious public health concerns. Albuterol has been reformulated in the non-ozone-depleting propellant, hydrofluoroalkane-134a (HFA albuterol). OBJECTIVES: The primary objective was to compare the safety of HFA albuterol to an albuterol product formulated in chlorofluorocarbon propellants (CFC albuterol) during 1 year of treatment in asthmatics. Bronchodilator efficacy of the two products was assessed as a secondary objective. METHODS: The results from two open-label, parallel-group trials of similar design in asthmatics requiring short-acting beta-agonists for symptom control were combined. Patients took two puffs bid of either HFA albuterol or CFC albuterol for 1 year. Additional puffs of study drug were allowed as needed to control asthma symptoms. Adverse events were recorded at clinic visits. Patients self-administered study drug at quarterly visits and underwent serial spirometry during a 6-h period postdose. Bronchodilator efficacy variables, based on FEV1 response to study drug, were proportion of responders, time to onset of effect, peak percent change, time to peak effect, duration of effect, and area under the curve. Differences between products and changes over time in efficacy variables were assessed using an analysis of variance model. Regression analyses with FEV1 as a covariate were performed post-hoc to analyze changes in bronchodilator efficacy over time. RESULTS: Demographic and baseline characteristics were similar for patients receiving HFA albuterol (n = 337) and CFC albuterol (n = 132). Total reported adverse events were similar for the two treatments. Differences in only four individual adverse events were noted: the HFA albuterol group reported more gastroenteritis and dizziness; the CFC albuterol group reported more epistaxis and expectoration. Adverse events attributed to study drug use were infrequent. No serious adverse events were related to study drug use. Predose FEV1 at quarterly visits increased to a small extent in both groups from month 0 to month 12. The bronchodilator efficacy of HFA albuterol was comparable to that of CFC albuterol at the quarterly visits, but decreased from baseline for both products over the 12 months of treatment. Use of inhaled corticosteroids, nasal corticosteroids, or theophylline did not explain the increase in predose FEV1 over time and did not protect patients from developing reduced bronchodilator efficacy by month 12. The change in predose FEV1 did not entirely account for the reduced bronchodilator efficacy over time. CONCLUSIONS: HFA albuterol has a safety profile similar to that of CFC albuterol during chronic, scheduled use, and both drugs are well tolerated. HFA albuterol and CFC albuterol provided comparable bronchodilator efficacy, but bronchodilator efficacy decreased for both products with 1 year of use.

Switching patients with asthma from chlorofluorocarbon (CFC) albuterol to hydrofluoroalkane-134a (HFA) albuterol.

Chlorofluorocarbon (CFC) propellants deplete stratospheric ozone. Production and use of CFCs, except for certain critical exemptions, has been prohibited by the Montreal Protocol. Use of CFCs as propellants in metered-dose inhalers (MDIs) is still allowed, but the U.S. Food and Drug Administration is planning the transition to alternative propellants for use in MDIs. Hydrofluoroalkane-134a (HFA), a non-ozone-depleting propellant, has been used to reformulate albuterol (HFA albuterol). This study evaluates whether comparable safety and efficacy continues for 12 weeks after patients with asthma are switched from CFC albuterol to HFA albuterol. Patients with asthma stabilized on CFC albuterol during a 12-week safety and efficacy trial were randomized to either continue receiving CFC albuterol or to be switched to receive HFA albuterol in a yearlong safety and efficacy trial. Safety and efficacy were compared over the first 12 weeks of the yearlong trial between patients who had remained on CFC albuterol and those who had been switched to HFA albuterol. Bronchodilator efficacy was evaluated by serial spirometry for 6 hr after the patients self-administered the study drug in the clinic. Safety was assessed by measuring changes in pulse rate, blood pressure, and electrocardiogram (ECG) intervals after dosing with study drug, monitoring adverse events, and performing prestudy and poststudy laboratory testing and physical examinations. No significant differences in bronchodilator efficacy between the patients continuing to receive CFC albuterol and those switched to HFA albuterol were found in the 12 weeks after the switch. No differences between the two products were found for changes in pulse rate, blood pressure, and ECG intervals. Adverse event profiles were similar for the two products, except the patients remaining on CFC albuterol reported increased asthma symptoms and rhinitis significantly more often than the patients switched to HFA albuterol. No clinically meaningful changes in laboratory tests or physical examinations were found in either treatment group. Patients with asthma switched from CFC albuterol to HFA albuterol receive comparable bronchodilation with a similar safety profile as those continuing to receive CFC albuterol.

Proventil HFA and ventolin have similar safety profiles during regular use.

OBJECTIVE: As a secondary objective to a long-term study evaluating the bronchodilator effectiveness of Proventil HFA (albuterol), to assess the safety of Proventil HFA, Ventolin, and hydrofluoroalkane 134a (HFA-134a) placebo over 12 weeks of regular dosing. DESIGN: Randomized, double-blind, double-dummy parallel group, placebo-controlled, multicenter trial of asthmatics requiring inhaled beta-adrenergic bronchodilators for symptom control. INTERVENTIONS: Treatment with Proventil HFA, Ventolin, or HFA-134a placebo, qid, for 12 weeks. MEASUREMENTS: Adverse events were reviewed at biweekly clinic visits. Between clinic visits, patients recorded morning and evening peak expiratory flow (PEF), asthma symptom and nighttime asthma sleep disturbance scores, and use of rescue beta-adrenergic bronchodilator on diary cards daily. Investigators provided a global assessment of asthma control at weeks 0, 4, 8, and 12. Vital signs were recorded over 6 h after dosing with study drug at weeks 0, 4, 8, and 12. Standard laboratory tests, CBC count, serum chemistries, and urinalysis were obtained at study start and end. RESULTS: Adverse event reporting rates were similar for the three treatment groups. The morning PEF tended to be lower for the Proventil HFA and Ventolin groups than the HFA-134a placebo group, but the evening PEF tended to be higher for the active treatment groups. Daytime asthma symptom scores tended to be lower (better) with active treatment than placebo, but nighttime asthma sleep disturbance scores were similar for all three treatment groups. Use of Ventolin Rotacaps as rescue medication was significantly greater for the HFA-134a placebo group than the Proventil HFA and Ventolin groups. Diary card data did not change within groups over time. Investigator global assessments of asthma scores clustered between fair and good for all three treatment groups throughout the study. Changes in heart rate and BP were small after dosing with study drug and tended to be similar for the active treatments and HFA-134a placebo groups. No clinically meaningful changes in results of standard laboratory tests were found in any treatment group during this study. CONCLUSIONS: Proventil HFA had a similar safety profile as Ventolin during regular use. A dosage of 16 puffs per day of propellant HFA-134a was well tolerated by asthmatics. Regular use of either Proventil HFA or Ventolin did not cause asthma control to deteriorate.

Proventil HFA provides bronchodilation comparable to ventolin over 12 weeks of regular use in asthmatics.

OBJECTIVE: To compare the bronchodilator effectiveness of albuterol reformulated in the chlorofluorocarbon-free propellant hydrofluoroalkane (HFA)134a (Proventil HFA) to that of Ventolin and HFA placebo over 12 weeks of regular dosing. DESIGN: Randomized, double-blind, double-dummy, parallel group, placebo-controlled, multi-center trial of asthmatics requiring inhaled beta-adrenergic bronchodilators for symptom control. INTERVENTIONS: Treatment qid with Proventil HFA, Ventolin, or HFA-134a placebo for 12 weeks. MEASUREMENTS: At weeks 0, 4, 8, and 12, spirometry was performed predose and serially over 6 h after dosing with study drug. Bronchodilator efficacy variables, based on FEV1 response to study drug, were proportion of responders, time to onset of effect, peak percent change, time to peak effect, duration of effect, and area under the curve (AUC). RESULTS: Demographic and baseline characteristics were similar for patients randomized to Proventil HFA (193), Ventolin (186), and HFA-134a placebo (186). No significant differences were found between the Proventil HFA and Ventolin treatment groups for any FEV1 efficacy variable, either predose or during 6 h of serial spirometry, at weeks 0, 4, 8, and 12. For all efficacy variables, except time to onset of effect, the Proventil HFA and Ventolin results were significantly greater than placebo. Time to onset of effect for the HFA-134a placebo group is misleading; only 13 patients (7%) were found to be responders in the intent-to-treat database. These efficacy results were found to be consistent across subgroup analyses of inhaled and nasal corticosteroid use, age (18 to 35 and 36 to 66 years), sex, race, weight (<60, 60 to 100, and >100 kg), and baseline FEV1 (< or =55% and >55% predicted). The peak FEV1 effect, duration of FEV1 effect, and AUC for FEV1 were all significantly smaller at weeks 4, 8, and 12 than week 0 for both the Proventil HFA and Ventolin treatment groups. CONCLUSIONS: Proventil HFA provided bronchodilation comparable to Ventolin and superior effects to HFA-134a placebo over 12 weeks of regular dosing. There was a diminution in bronchodilator response to both Proventil HFA and Ventolin after 4 weeks of use.

Cumulative dose response study comparing HFA-134a albuterol sulfate and conventional CFC albuterol in patients with asthma.

BACKGROUND: As a result of the pending ban on chlorofluorocarbon production, the non-chlorofluorocarbon propellant 1,1,1,2-tetrafluoroethane (HFA-134a) is being evaluated as a replacement for CFCs in metered-dose inhalers. OBJECTIVES: This cumulative dose response study compared the safety and bronchodilator efficacy of 16 cumulative inhalations of albuterol sulfate in an HFA-134a, CFC-free propellant system (108 microg of albuterol sulfate, equivalent to 90 microg of albuterol base) with that of equivalent doses of albuterol in a conventional CFC propellant system. METHODS: Twenty-two patients with at least a 12-month history of stable asthma, who were currently taken an inhaled beta-adrenergic bronchodilator, and who had a FEV1 between 40% and 80% of predicted, were enrolled in this randomized, modified-blind, two-period crossover study. One, 1, 2, 4, and 8 inhalations of study drug were self-administered at 30-minute intervals, resulting in 16 cumulative inhalations. Pulmonary function and safety measures were assessed after each dosing interval. RESULTS: A significant dose response was found for HFA-134a albuterol sulfate and CFC albuterol with regard to changes in FEV1, serum potassium, heart rate, and blood pressure after 16 cumulative inhalations. No significant differences were demonstrated between HFA-134a albuterol sulfate and CFC albuterol for any FEV1 or safety parameter at any cumulative dose level. No clinically meaningful laboratory or physical examination abnormalities were found with administration of either HFA-134a albuterol sulfate or CFC albuterol. CONCLUSIONS: HFA-134a albuterol sulfate provides bronchodilation comparable to CFC albuterol and has a similar safety profile.

Proventil HFA provides protection from exercise-induced bronchoconstriction comparable to proventil and ventolin.

INTRODUCTION: During the 1970s, scientists suggested that the growing use of chlorofluorocarbons (CFCs) was contributing to depletion of the stratospheric ozone layer with potentially harmful results. A committee on the ozone layer organized the preparation of the Montreal Protocol. This protocol mandated the cessation of production and use of CFCs by January 1, 1996. The primary exemption to this ban is for the use of CFCs as propellants in metered dose inhalers (MDIs) for the treatment of asthma. Suitable replacement hydrofluoroalkane (HFA) propellants, such as HFA-134a, for use in MDIs have been identified. Albuterol, a selective beta-adrenergic agonist, currently widely available for inhalation asthma therapy, has been reformulated in HFA-134a (Proventil HFA). OBJECTIVE; To compare the efficacy of Proventil HFA to Ventolin, Proventil, and placebo (HFA-134a) MDI in protecting asthmatic patients from exercise-induced bronchoconstriction. METHODS: This was a randomized, single-blind, placebo-controlled, 4-period crossover study of asthmatic patients with documented exercise-induced broncho-constriction. Twenty patients self administered two puffs of either Proventil HFA, Ventolin, Proventil or placebo, from an MDI, 30 minutes prior to performing a standardized exercise challenge at the study site. Spirometry was performed predose and 5, 10, 15, 30, 45, 60, 75, and 90 minutes after completion of the exercise challenge. Heart rate and blood pressure were measured just prior to spirometry and a 12-lead ECG was performed 15 minutes after completion of the exercise challenge for measurement of the QT corrected interval. RESULTS: The primary efficacy variable was the smallest percent change from the predose FEV1 following exercise. The smallest percent change from predose FEV1 for Proventil HFA was 2.0 +/- 9.9 SD, similar to the 2.0 +/- 11.4 SD for Ventolin, and the 3.6 +/- 10.2 SD for Proventil. The smallest percent change from predose FEV1 for each of the active treatments was significantly different from placebo, -23.7 +/- 14.5. Twelve of the patients had a > or = 20% fall in FEV1 post-exercise with placebo pretreatment, but only 1, 1, and 0 had > or = 20% FEV1 falls after treatment with Proventil HFA, Ventolin, and Proventil respectively. Changes in heart rate, blood pressure and QT corrected interval were similar for the three active treatments following exercise. CONCLUSIONS: Proventil HFA provides protection against exercise-induced bronchoconstriction comparable to Ventolin and Proventil and protection superior to placebo. Proventil HFA has a safety profile similar to Ventolin when used to prevent exercise-induced bronchoconstriction.

Exaggerated pulmonary hypertension with monocrotaline in rats susceptible to chronic mountain sickness.

Hilltop (H) strain Sprague-Dawley rats are more susceptible to chronic mountain sickness than are the Madison (M) strain rats. It is unclear what role pulmonary vascular remodeling, polycythemia, and hypoxia-induced vasoconstriction play in mediating the more severe pulmonary hypertension that develops in the H rats during chronic hypoxia. It is also unclear whether the increased sensitivity of the H rats to chronic mountain sickness is specific for a hypoxia effect or, instead, reflects a general propensity toward the development of pulmonary hypertension. Monocrotaline (MCT) causes pulmonary vascular remodeling and pulmonary hypertension. We hypothesized that the difference in the pulmonary vascular response to chronic hypoxia between H and M rats reflects an increased sensitivity of the H rats to any pulmonary hypertensive stimuli. Consequently, we expected the two strains to also differ in their susceptibility to MCT-induced pulmonary hypertension. Pulmonary arterial pressures in conscious H and M rats were measured 3 wk after a single dose of MCT, exposure to a simulated high altitude of 18,000 ft (barometric pressure = 380 mmHg), and administration of a single dose of saline as a placebo. The H rats had significantly higher pulmonary arterial pressures and right ventricular weights after MCT and chronic hypoxia than did the M rats. The H rats also had more pulmonary vascular remodeling, i.e., greater wall thickness as a percentage of vessel diameter, after MCT and chronic hypoxia than did the M rats. The H rats had significantly lower arterial PO2 than did the M rats after MCT, but the degree of hypoxemia was mild [arterial PO2 of 72.5 +/- 0.8 (SE) Torr for H rats vs. 77.4 +/- 0.8 Torr for M rats after MCT]. The H rats had lower arterial PCO2 and larger minute ventilation values than did the M rats after MCT. These ventilatory differences suggest that MCT caused more severe pulmonary vascular damage in the H rats than in the M rats. These data support the hypothesis that the H rats have a general propensity to develop pulmonary hypertension and suggest that differences in pulmonary vascular remodeling account for the increased susceptibility of H rats, compared with M rats, to both MCT and chronic hypoxia-induced pulmonary hypertension.