Intrapleural Dornase and Tissue Plasminogen Activator in pediatric empyema (DTPA): a study protocol for a randomized controlled trial.

BACKGROUND: A randomized controlled trial of adults with empyema recently demonstrated decreased length of stay in hospital in patients treated with intrapleurally administered dornase alfa and fibrinolytics compared to fibrinolytics alone. Whether this treatment strategy is safe and effective in children remains unknown. METHODS/DESIGN: This study protocol is for a superiority, placebo-controlled, parallel-design, multicenter randomized controlled trial. The participants are previously well children admitted to a children's hospital with a diagnosis of empyema requiring chest tube insertion and fibrinolytics administered intrapleurally. Children will be randomized after the treating physician has decided that pleural drainage is required but prior to chest tube insertion. After chest tube insertion, participants in the treatment group will receive intrapleurally administered tissue plasminogen activator (tPA) 4 mg followed by dornase alfa 5 mg. Participants in the placebo group will receive tPA 4 mg followed by normal saline. Study treatments will be administered once daily for 3 days. All participants, parents or caregivers, clinicians, and research personnel will remain blinded. The primary outcome is length of stay from chest tube insertion to discharge from hospital. Secondary outcomes include time to meeting discharge criteria, chest tube duration, fever duration, need for additional procedures, adverse events, hospital readmission, cost of hospitalization, and mortality. DISCUSSION: This multicenter randomized controlled trial will assess the safety, effectiveness, and cost-effectiveness of combined treatment with dornase alfa and fibrinolytics compared to fibrinolytics alone for the treatment of empyema in children. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01717742 . Registered on 8 October 2012.

Recombinant human deoxyribonuclease shortens ventilation time in young, mechanically ventilated children.

Recombinant human deoxyribonuclease I (dornase alfa) is currently used as an inhaled mucoactive agent in the treatment of cystic fibrosis. In a randomized, placebo-controlled, double-blind clinical study in 100 infants, we investigated whether the therapeutic use of dornase alfa can be extended to ventilated, fluid-restricted children to reduce reintubation rate, ventilation duration, pediatric intensive care unit (PICU) stay, and ventilation complications. While reintubation rates were similar for dornase alfa 7% vs. placebo 9% (odds ratio, 0.77; confidence interval, 0.11-4.9), the incidence of atelectasis (6 vs. 17, respectively; P-value 0.051), median ventilation time (2.2 vs. 3.4 days, respectively; P-value 0.043), median length of PICU stay (7 vs. 8 days, respectively; P-value 0.051), and mean costs (4,830 vs. 6,320, respectively) were lower in the dornase alfa group. No adverse effects were observed, even in critically ill patients. We found that dornase alfa was beneficial and safe. Our findings also indicate that dornase alfa is possibly of value from the first day of mechanical ventilation onward, particularly when longer ventilation (>3 days) is expected in fluid-restricted children after cardiac surgery.

Innovative assessment of inpatient and pulmonary drug costs for children with cystic fibrosis.

BACKGROUND: Previous estimates of the cost of care for pediatric Cystic fibrosis (CF) showed wide variation, without specific summary of pulmonary drug costs. METHODS: Enrolled CF children from the Wisconsin newborn screening trial were evaluated quarterly per protocol. Assessments systematically included all treatments, hospitalizations, and nutritional and pulmonary outcomes. Direct medical costs from hospital billing and medical records from 1989 to 2010 were used to describe costs by age-ranges and subgroups throughout follow-up. Outpatient drugs were separated by category (pulmonary/otherwise). Inpatient and drug costs were examined by clinical risk factors (presence of meconium ileus, pancreatic insufficiency, and expected severity of genetic mutations). RESULTS: Seventy-three children were followed for an average of 12.9 years with an average annual total cost of care of $24,768. Outpatient drug costs (53%) and hospitalizations (32%) represented the majority of costs. Drug costs were 48% for pulmonary indications and 52% for non-pulmonary. Pulmonary drug costs for children taking dornase were 54% of their drug costs while pulmonary drug costs were only 31% for children not taking dornase. Significant differences in frequency of inpatient stays existed for children with pancreatic insufficiency. Substantial differences in treatment costs exist as children age and by clinical risk factor. CONCLUSION: This study provides more accurate longitudinal estimates of CF care costs throughout childhood and shows that increasing age, pancreatic insufficiency, use of dornase, and hospitalizations are key determinants of cost. These estimates can be included in evaluations of the cost-effectiveness of new, highly expensive treatments being introduced for any CF population. Pediatr Pulmonol. 2016;51:1295-1303. © 2016 Wiley Periodicals, Inc.

Dornase alfa: a new option in the management of cystic fibrosis.

Recombinant human DNase I, or dornase alfa, is the first new therapy developed specifically for cystic fibrosis in almost 30 years. It selectively digests extracellular DNA and reduces the viscosity of purulent sputum. In clinical trials dornase alfa modestly improved pulmonary function, slightly decreasing the number of respiratory exacerbations requiring parenteral antibiotics compared with placebo. Phase III studies suggest that patients receiving dornase alfa also spend slightly fewer days in the hospital than those treated with placebo. The aerosolized preparation is safe and generally well tolerated. Voice alteration and sore throat are the most commonly reported adverse effects. Further research is necessary to determine the optimum time to initiate therapy and to evaluate the agent's pharmacoeconomic impact on the treatment of cystic fibrosis. Aerosolized dornase alfa should always be given in conjunction with standard cystic fibrosis therapies including antibiotics, chest physiotherapy, and pancreatic enzyme supplementation.

Dornase alfa. A review of pharmacoeconomic and quality-of-life aspects of its use in cystic fibrosis.

Cystic fibrosis (CF) is a fatal hereditary disease; patients with CF have an average lifespan of 30 years. By cleaving neutrophil-derived DNA, dornase alfa (recombinant human deoxyribonuclease I) decreases the adhesiveness and visco-elasticity of sputum in the infected lungs of patients with CF. As a result, respiratory function is improved in patients with all degrees of disease severity, and the relative risk of pulmonary exacerbations is reduced in patients with mild to moderate disease. Resource utilisation (days spent in hospital or receiving parenteral antibiotics) in patients with mild to moderate disease is also reduced by dornase alfa, as evidenced by a placebo-controlled trial in > 900 patients. Cost savings generated by these reductions in resource use during 24 weeks of dornase alfa therapy offset about 17 to 37.5% of the acquisition cost of the drug, depending on local cost data for various countries. Reductions in resource utilisation with dornase alfa have not been observed in patients with severe disease. Available cost-effectiveness and cost-utility analyses are not fully published. One analysis estimated that the incremental cost of avoiding one hospitalisation was about $Can 15,000 relative to standard therapy after 1 year of treatment. Informal analysis in the UK suggests a cost per quality-adjusted life-year of 25,000 Pounds for dornase alfa. Some quality-of-life (QOL) domains (mainly cough frequency and chest congestion) have shown modest improvement in patients treated with dornase alfa, mainly those with mild CF. Persuasive evidence of QOL benefit is lacking in those with more severe disease. Identifying patients most likely to benefit from dornase alfa therapy is essential to maximise clinical and cost benefits. The lack of a demonstrated reduction in resource utilisation in patients with severe CF makes its use more difficult to justify economically in this group than in those with less severe disease. However, in the absence of other treatments for this group, economic considerations must be weighed against clinical benefits. In conclusion, the acquisition cost of dornase alfa is partially offset by savings gained by reducing resource utilisation in patients with mild to moderate CF, and the drug appears to improve quality of life in some patients, mostly those with less severe disease. However, in the absence of guidance from definitive cost-effectiveness analyses, individual healthcare providers must make their own decisions about how best to provide dornase alfa to patients with CF in a rational and cost-justifiable manner.

Cystic fibrosis: cost of illness and considerations for the economic evaluation of potential therapies.

Cystic fibrosis (CF) is the most common life-shortening inherited disease of the Caucasian race, with a prevalence of around 1 in 2500 live births. Advances in the treatment and management of respiratory and pancreatic disorders have dramatically increased the life expectancy of patients with CF. This article presents an overview of cost-of-illness studies of CF, identifies deficits in the available health economic analyses of CF and discusses which specific factors are essential for the economic evaluation of potential therapies, based on a critical review of the health economic literature on two main therapeutic strategies. Cost-of-illness studies of CF have predominantly been restricted to direct costs. According to the literature, direct costs amount to between 6200- 16300 US dollars (1996 values) per patient per year. As most studies likely underestimated the actual costs (e.g. by disregarding provision of certain healthcare services), real healthcare costs tend to be at the upper end of the cost range. Healthcare costs depend on the patient's age (for adults, costs are approximately twice as high as for children), the grade of severity (the cost relationship of severe to mild CF is between 4.5 and 7.1) and other factors. Lifetime direct costs of CF are estimated at 200 000-300000 US dollars (at 1996 values and a discount rate of 5%). Home intravenous (IV) antibacterial therapy and recombinant human DNase (rhDNase; dornase alfa) treatment are the two main therapeutic strategies most often evaluated in health economic studies of CF. While home IV antibacterial therapy (compared with inpatient IV antibacterial therapy) is assumed to be cost saving, rhDNase treatment is a very cost-intensive therapy intended to efficiently achieve health improvements. Health economic analyses of future CF therapeutic technologies should present explicit data regarding healthcare services provision, resource consumption and unit costs. Indirect costs and patient costs should be considered more often than they have to date, particularly when they are significantly influenced by novel CF technologies. The perspective of health economic studies should be stated explicitly and always include the societal perspective. More economic studies should be based on a controlled, and preferably randomised, design. The observation period must be long enough to identify long-term effects of interventions. A greater number of effectiveness studies should be performed to determine costs and outcomes of therapies applied under everyday life conditions for patients with CF. Finally, international comparison studies should identify the influence of different healthcare systems on the costs and outcomes of interventions.

[Socioeconomic evaluation of the effect of rhDNase on the cost of treating infections of the respiratory tract in patients with cystic fibrosis]. / Sozioökonomische Evaluation des Einflusses von rhDNase auf die Kosten der Behandlung von Infektionen der Atemwege bei Patienten mit zystischer Fibrose.

BACKGROUND: Data from a multicenter, placebo-controlled, double-blind, parallel clinical trial on the use of aerosolized recombinant human DNase (rhDNase), known as Pulmozyme produced by Genentech, about the treating of respiratory-tract infections among patients with cystic fibrosis (CF), has been used to evaluate possible economic effects by identifying the direct medical costs. To calculate the cost an intention-to-treat approach has been used. PATIENTS AND METHOD: The patients were randomly placed in one of three treatment groups. The first group was treated with a 2.5 mg dose of rhDNase and one dose of placebo daily, the second group with placebo twice a day. The third patient group (treated with a 2.5 mg dose of rhDNase twice a day) was not included in this study. RESULTS: The main measurements of resource utilization of services for treatment of respiratory-tract infections were the number of hospitalizations in the follow-up period of 24 weeks (0.41 rhDNase once daily, 0.56 placebo), the number of total days in hospital (4.9 rhDNase, 6.4 placebo), the number of total days of outpatient intravenous antibiotic therapy (2.9 rhDNase, 4.4 placebo), the number of total days of inpatient intravenous antibiotic therapy (4.8 rhDNase, 6.2 placebo), the number of total days of outpatient oral antibiotic therapy (23.5 rhDNase, 25.2 placebo) and the number of total days of inpatient oral antibiotic therapy (0.59 rhDNase, 0.55 placebo). From a health insurance perspective the total direct cost based on a weighted per diem for German CF-centres was 5,879 DM (rhDNase) vs 7,849 DM (placebo) per patient respectively. Costs of antibiotics were estimated using all available information on the consumption of antibiotic drugs revealing 2,954 DM per patient in the rhDNase-group and 4,213 DM in the placebo-group. The large cost differences remain also true in a sensitivity analysis introducing minima and maxima as key factors. CONCLUSION: As a result of this study we conclude that the use of rhDNase in treatment of respiratory-tract infections in patients with cystic fibrosis is cost saving and less burdened for the patients. However, all cost estimates do not include the cost of rhDNase itself, which are DM 9,094 for the period of follow-up.

Dornase alpha and survival of patients with cystic fibrosis.

Dornase alpha can offer substantial clinical benefits to cystic fibrosis patients, but its long-term impact is as yet unknown. This article attempts to model the impact of continuous dornase alpha use on patient survival and its cost implications for the health-care provider.

Nationwide trends in the medical care costs of privately insured patients with cystic fibrosis (CF), 2001-2007.

BACKGROUND: Longer survival of patients with cystic fibrosis (CF) has been linked to initiation of national newborn screening, new therapies that prevent and treat pulmonary exacerbations, and closer monitoring of health outcomes. However, few studies have examined the economic impact of these medical advances on costs, and none have examined these costs longitudinally. METHODS: We used a nationwide database of the healthcare claims of privately insured individuals with CF between 2001 and 2007. Study subjects had at least two claims with diagnoses of CF (ICD-277.xx). We extracted inpatient admissions, outpatient visits, prescribed therapies, and screening procedures and then calculated all-cause medical utilization and annual medical costs, adjusted for inflation. We adjusted for comorbidity burden and tested longitudinal time trends using regression models. RESULTS: We identified 3,273 individuals with CF. Overall, the costs of prescription drugs, outpatient visits, and durable medical equipment increased by 59% during the 7-year period ($18,715 in 2001 vs. $29,718 in 2007, P < 0.001). The proportion of individuals hospitalized increased from 24.0% to 38.9%, P < 0.001. Annual testing of pulmonary function increased 53% (49.9% in 2001 to 76.3% in 2007, P < 0.001) and respiratory cultures more than doubled (27.9-67.5%, P < 0.001). Use of CF-related therapies also significantly increased (dornase alfa, 32.1-52.4%, P < 0.001; oral antibiotics, 54.1-71.8%, P = 0.007). Analyses by age showed the largest increases in total medical care costs occurred for the oldest CF patients (aged >30; $20,536 in 2001 to $56,116 in 2007, P < 0.001) and the youngest (aged <11; $3,060 in 2001 to $31,723 in 2007, P < 0.001). CONCLUSIONS: Although improvements in diagnosis and treatment have yielded substantial benefits, they have come at considerable cost, both in terms of treatment burden and healthcare dollars.

A cost-effectiveness analysis of rhDNase in children with cystic fibrosis.

OBJECTIVES: This study compared the relative cost-effectiveness of daily recombinant human deoxyribonuclease (rhDNase), with alternate day rhDNase and hypertonic saline (HS) for treating children with cystic fibrosis (CF). METHODS: A randomized controlled trial with a crossover design allocated 40 CF children consecutively to 12 weeks of daily rhDNase, alternate day rhDNase, or HS. The primary outcome measure was forced expiratory volume in 1 second (FEV1), a measure of lung function. All health resource use was prospectively documented for each patient and multiplied by unit costs to give a total health service cost for each 12-week treatment period. The nonparametric bootstrap method was used to present cost-effectiveness acceptability curves and net benefit statistics for each treatment comparison, for various hypothetical levels of the decision maker's ceiling ratio. RESULTS: Compared with HS, there was a 14% improvement in FEV1 for daily rhDNase (95% Cl, 5% to 23%), and a 12% improvement (95% Cl, 2% to 22%) for alternate day rhDNase. For a ceiling ratio of 200 pounds sterling per 1% gain in FEV1, the mean net benefits of daily and alternate day rhDNase compared with HS were 1,158 pounds sterling (95% Cl, -621pounds sterling to 2,842) and 1,188 pounds sterling (95% Cl, -847 to 3,343), respectively; the mean net benefit of daily compared with alternate day rhDNase was -30 pounds sterling (95% Cl, -2,091 pounds sterling to 1,576). CONCLUSIONS: If decision makers are prepared to pay 200 pounds sterling for a 1% gain in FEV1 over a 12-week period, then on average either rhDNase strategy is cost-effective.

Using disease registries for pharmacoepidemiological research: a case study of data from a cystic fibrosis registry.

BACKGROUND: The Epidemiologic Registry of Cystic Fibrosis (ERCF) was a multicentre, longitudinal follow-up project of cystic fibrosis patients enrolled at some 200 centres in nine European countries between 1994 and 1999. PURPOSE: We aimed to assess and improve the quality of a subset of data from the ERCF relating to seven English centres (1184 patients), prior to using the data for a long-term cost-effectiveness analysis of dornase alfa (Pulmozyme). Specifically we wanted to assess the completeness and accuracy of the data and the comparability of cases across centres. METHODS: We used a subset of ERCF data relating to seven UK cystic fibrosis (CF) centres. Following initial data editing, key variable data from a sample of patients from five centres were subjected to a detailed verification of ERCF data against original data sources available in the centres. Disagreements between ERCF reports and original data sources were identified and corrected in the study dataset. In addition, centre staff were questioned about relevant clinical and recording practices. RESULTS: Thanks to detailed routine data checking procedures on key variables operated by the ERCF, the rates of disagreement between ERCF data and original data as identified in our verification process on the assessed variables are generally low (0.4-3.7%). Some outcome variables (deaths, hospitalisations) seem to be under-reported by some centres. Episodes of pulmonary exacerbation are difficult to identify and also to verify. Twenty-four patients were registered twice (consecutively in two different centres). There were some differences between centres in their interpretation of recording rules. CONCLUSIONS: Researchers seeking to use disease registry data should consider detailed data quality review processes. Apart from data accuracy, reliable definitions of both critical events as well as their timing are important. The degree of under-reporting, particularly of outcome variables, should be estimated. Information on local clinical and reporting practices is necessary to interpret multi-centre data. Data protection issues may limit the possibilities for detailed data quality assessments of secondary data, as does the accessibility of original data for verification purposes. Our experiences and recommendations may be valuable for those intending to use disease registry data as well as those devising and operating such registries.

Aerosolized dornase alpha (rhDNase) in cystic fibrosis.

Advances in the treatment and management of respiratory and pancreatic disorders has increased the life expectancy of patients with cystic fibrosis to 28 years (1). Despite the use of potent antibiotics and chest physiotherapy, persistent bacterial infection of the lung is the major cause of morbidity and mortality in these patients (2). This occurs, in part, because of the production of copious amounts of pulmonary secretions. It has been found that these secretions contain high amounts of human DNA (3-8). This high DNA concentration causes two problems. First, it increases the viscosity of sputum. This, in conjunction with reduced mucociliary clearance, decreases the removal of sputum. Second, the DNA binds to aminoglycosides, which decreases their antimicrobial efficacy (9, 10). Until recently there was no effective drug to decrease the viscosity of sputum in patients with cystic fibrosis. Dornase alpha (Pulmozyme) is the first drug to offer a safe and effective method to treat excessive DNA in sputum. In vitro studies demonstrated that rhDNase greatly decreased the viscosity of sputum by decreasing the concentration of DNA in a concentration-dependent manner (11).

The role of dornase alfa in the treatment of cystic fibrosis.

OBJECTIVE: To review the current utility and proper role of dornase alfa (recombinant human DNase or rhDNase), which has been approved for use in cystic fibrosis. Several aspects related to these issues are addressed including the drug's mechanism of action, administration and dosing, and clinical safety and efficacy. We also critically examine the agent's role in the treatment of cysti fibrosis and consider the controversies involved with its use. DATA SOURCE: A MEDLINE search was conducted to identify pertinent literature, including review articles and clinical trials. STUDY SELECTION: Studies examining the efficacy and safety of dornase alfa in patients with cystic fibrosis. DATA EXTRACTION: Results from published, prospective, randomized trials are presented and critiqued. DATA SYNTHESIS: Production of viscous respiratory secretion is a hallmark phenomenon of cystic fibrosis, leading to a variety of symptoms. Dornase alfa targets this symptom and decreases the viscosity of these secretions. Clinical trials have indicated a small but statistically significant improvement in forced expiratory volume in 1 second and forced vital capacity. Enhancement in a patient's dyspnea and quality of life has varied between the trials, with few of the studies noting no statistically significant improvement. Adverse reactions are minimal and did not result in any patient withdrawals from the trials. A positive impact on infection rates, length of hospitalization, and need for intravenous antibiotic therapy was noted in one trial. However, reports of similar results have not yet been published, and thus the clinical significance or impact of this phenomenon is not fully understood. Moreover, results of more long-term use and in patients whose conditions are less stable have yet to undergo the scrutiny of peer/editorial review. Administration of the drug, which must be maintained continuously, is relatively expensive. CONCLUSIONS: Dornase alfa appears to produce small but sustained improvements in lung function in patients with cystic fibrosis. It may also slow the progression of pulmonary disease. Infection rates appear to be reduced, which may well have important long-term consequences. However, evidence to date has not clarified the most appropriate use of dornase alfa in the treatment of cystic fibrosis. Whether quality of life is affected in a meaningful and measurable way is yet to be clarified. A trial of the drug in patients with cystic fibrosis who have obvious lung disease is reasonable, but continued treatment should be based on clear clinical response. Therefore, questions about the drug's exact role in the overall management of cystic fibrosis remain to be answered. Although benefits received may not prove to be cost-effective, long-term effects on disease progression may well justify use of this agent.

A multinational economic evaluation of rhDNase in the treatment of cystic fibrosis.

Economic evaluations of pharmaceuticals are increasingly being conducted in conjunction with randomized phase III clinical trials to meet the demand for pharmacoeconomic data when new products are launched. While the need for such data is often global, the trials in which relevant information may be collected are often conducted in only one or a limited number of countries. A critical issue is how data from pivotal clinical trials in one setting can serve as the basis for pharmacoeconomic evaluations in others. We address this issue and report on four economic evaluations that we undertook in conjunction with a recent U.S. phase III clinical trial of recombinant human deoxyribonuclease (rhDNase), which is used to improve pulmonary function in patients with cystic fibrosis (CF). The objective of these evaluations was to estimate the potential impact of rhDNase therapy in France, Germany, Italy, and the United Kingdom on the direct costs of medical care for the treatment of respiratory tract infections (RTIs) in patients with CF. Analyses of economic impact were undertaken both with and without adjustment for differences in practice patterns between the United States and the countries of interest. Our findings suggest that rhDNase therapy may reduce the cost of RTI-related care by between US$600 and US$1,100 over a 24-week period; the cost of rhDNase is not included in these figures, as a price was unavailable when our analyses were undertaken. Despite methodologic challenges, economic evaluations that meet the information needs of decision makers in diverse countries can nonetheless be undertaken in conjunction with phase III clinical trials.

Effects of hypertonic saline, alternate day and daily rhDNase on healthcare use, costs and outcomes in children with cystic fibrosis.

BACKGROUND: Daily recombinant human deoxyribonuclease (rhDNase) is an established but expensive treatment in cystic fibrosis (CF). An alternative lower cost therapy is hypertonic saline (HS), which has been shown to improve lung function in short term studies. This study compares the costs and consequences of daily rhDNase with alternate day rhDNase and HS in children with CF. METHODS: In an open, randomised, crossover trial, 48 children with CF were allocated consecutively to 12 weeks of once daily 2.5 mg rhDNase, alternate day 2.5 mg rhDNase, and twice daily 5 ml 7% HS. Outcomes assessed included forced expiratory volume in 1 second (FEV(1)) and quality of life. All healthcare resource use was prospectively recorded for each patient. Unit costs were collected and combined with resource use data to give the total health service costs per patient for each treatment strategy. RESULTS: Daily rhDNase resulted in a significantly greater increase in mean FEV(1) than HS (8%, 95% CI 2 to 14) but there was no significant difference in FEV(1) between daily and alternate day rhDNase (2%, 95% CI -4 to 9). Over a 12 week period the mean incremental costs of daily rhDNase compared with HS was pound 1409 (95% CI pound 440 to pound 2318), and the incremental cost of using daily rather than alternate day rhDNase was pound 513 (95% CI - pound 546 to pound 1510). CONCLUSIONS: Daily rhDNase is more effective than 5 ml 7% HS twice daily delivered by jet nebuliser, but significantly increases healthcare costs. Administering rhDNase on an alternate day rather than a daily basis is as effective, with a potential for cost savings.

Use of rhDNase therapy and costs of respiratory-related care in patients with cystic fibrosis.

OBJECTIVE: To assess the relationship between level of use of recombinant deoxyribonuclease I (rhDNase) therapy and costs of respiratory-related care in patients with cystic fibrosis. DESIGN: Retrospective, cohort study using healthcare claims data from a large New England health insurer. PATIENTS: All cystic fibrosis patients five years of age and older who began therapy with rhDNase in 1994 (the year it was first marketed in the US). Healthcare claims were compiled for six months prior to first receipt of rhDNase (pretreatment) and for 30 months subsequently (follow-up). Patients were stratified according to their level of rhDNase use during follow-up, based on whether it was above or below the median number of therapy days for the sample. MAIN OUTCOME MEASURES: Costs of rhDNase, all antibiotics, and all respiratory-related outpatient (physician, home health, hospital outpatient) and inpatient care were included. All costs were expressed on an annualized basis. RESULTS: Twenty-four patients with cystic fibrosis who began treatment with rhDNase in 1994 met all entry criteria; the median number of therapy days over a 30-month period was 355. Among patients with low (i.e., below the median) rhDNase use (n = 12), mean +/- SD annualized costs of respiratory-related care increased by almost $17,000 between pretreatment and follow-up, from $29,251 +/- $37,919 to $46,109 +/- $40,944. Among high-use patients (n = 12), costs decreased by approximately $2500, from $37,178 +/- $48,476 to $34,592 +/- $22,591. The change in both groups was accounted for primarily by a change in the number of respiratory-related hospitalizations. CONCLUSIONS: Prolonged use of rhDNase may reduce costs of respiratory-related care in patients with cystic fibrosis; further study is required, however, to confirm these findings.