Dornase alfa in young patients with cystic fibrosis

LETTERS Dornase alfa in young patients with cystic fibrosis To the Editor: Quan et al concluded that dornase alfa maintained lung function and decreased respiratory exacerbations (RTEs) in children with cystic fibrosis (CF).1 However, the differences in pulmonary function changes and RTEs between the dornase alfa and placebo groups were small and of questionable clinical importance. Therefore, I agree with Dr Coates, who in his accompanying editorial,2 suggests that this study does not answer whether we should prescribe dornase alfa for these younger children with CF. In this pharmaceutical companysponsored multicenter study, 474 younger children (mean age, 8 years) with relatively normal lung function took either placebo or nebulized dornase alfa for two years. The children who received dornase alfa had a slightly less decline in the forced expired volume in 1 second (FEV1) and the forced expiratory flow between 25% and 75% of vital capacity (FEF25-75). However, the changes in FEV1 and FEF25-75 were so small that they easily fell within the inherent variability of these tests. At the end of the 2-year study, the difference in the change in FEV1 between the two groups was 3% predicted. The test-to-test variability of the FEV1 is 5% to 15%,3-5 so a patient with a baseline FEV1 of 95% predicted has a minimum variability of that value of ± 5% predicted. The FEF25-75 has even more variability, with 10% being an extremely conservative value.3-5 The difference in the 2-year change in FEF25-75 between the two groups was 8% predicted. For a patient with a baseline FEF25-75 of 85% predicted the inherent variability is at least ± 8.5% predicted. Thus, for any individual patient it would be nearly impossible to determine whether these small changes in FEV1 and FEF25-75 were the result of dornase alfa or the normal variability of the pulmonary function tests. The authors also concluded that dornase alfa decreased RTEs, but they did not state their criteria for diagnosing RTEs or categorize the severity of the RTEs. The rates of RTEs were fairly 838

low in both groups (24% for placebo, 17% for dornase alfa), and without knowing the severity of each of the RTEs we cannot determine the clinical relevance of this difference. Unfortunately, the study by Quan et al1 does not provide convincing evidence in favor of the long-term use of dornase alfa, an extremely expensive medication with a time-consuming delivery method, in younger children with CF who have relatively normal lung function. Col Edward R. Carter, MD Department of Pediatrics Madigan Army Medical Center Tacoma, WA 98431 9/35/128748 doi:10.1067/mpd.2002.128748

REFERENCES 1. Quan JM, Tiddens HA, Sy JP, McKenzie SG, Montgomery MD, Robinson, PJ, et al. A two-year randomized, placebo-controlled trial of dornase alfa in young patients with cystic fibrosis with mild lung function abnormalities. J Pediatr 2001;139:813-20. 2. Coates AL. What is the cystic fibrosis clinician supposed to do with human recombinant dornase alfa? J Pediatr 2001;139:768-70. 3. Cochrane GM, Prieto F, Clark TJH. Intrasubject variability of maximal expiratory flow volume curve. Thorax 1977;32:171-6. 4. Pennock BE, Rogers RM, McCaffree DR. Changes in measured spirometric indices. Chest 1981;80:97-9. 5. Lebowitz MD, Knudson RJ, Robertson G, Burrows B. Significance of intra-individual changes in maximum expiratory flow volume and peak expiratory flow curves. Chest 1982;81:566-70.

Reply To the Editor: Patients were required to perform pulmonary function tests reproducibly according to American Thoracic Society (ATS) standards for inclusion in the study. However, the reproducibility of FEV1 for an individual subject (within-subject variability) is distinct from the variability for a population

measure. The ATS criterion for reproducibility during pulmonary function testing states that repeat measurements for the same subject should be within 5% or 200 mL of each other. That is, a variability of <5% is recognized as acceptable for repeat measurements for the same subject at a single sitting. This criterion is not meant to apply to differences between populations. In this case, the variability for the population mean should be used to assess differences between the two treatment groups, and not the within-subject variability. The finding in this large study that a 3% predicted difference in FEV1 between the dornase alfa and placebo groups was highly significant (P = .006) indicates that it is highly unlikely that such a finding is the result of chance. The issues of the magnitude and clinical importance of the difference seen in FEV1 between these populations should be considered in light of previous studies. Most large trials conducted previously in CF have used the relative change from baseline as an endpoint rather than absolute change in percent predicted values.1,2 These trials have been of shorter (6 months) duration and included patients with a wide range of lung function at baseline, so calculation of the relative change was used to normalize changes in FEV1% predicted to the value at baseline. The equation for relative change is:

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Relative change = FEV1% predicted at end of treatment – FEV1% predicted at baseline  100 FEV1% predicted at baseline

The longer (2 years) duration and more uniform lung function at baseline in our study led us to define the treatment effect as the absolute difference: FEV1% predicted at end of treatment – FEV1% predicted at baseline. In fact, the relative change of 12% in the study by Ramsey et al2 is equivalent to an absolute difference of approximately 6% predicted in FEV1, and the relative change of 5.7% in the study by Fuchs et al1 is equivalent to an absolute difference of approximately 3.5% predicted in FEV1. The 3.2% treatment ef-