“Inferiority Complex” for a Reason

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pubertal staging and the final stature of the patients were unknown.

The assumption of the authors that atomoxetine has minimal or no effect on growth among pediatric patients seems to us unsupported, because the studies were not designed at the beginning to answer this question. We think also that, to assess the stimulant medication effect on height growth in children,2_{longer-term studies are} needed, looking at the rate of progression of the bone age and pubertal development.

Pietro Panei, MD Anne-Laure Knellwolf, MD Romano Arcieri, PhD Stefano Vella, MD

Department of Drug Research and Evaluation Italian National Institute of Health 00161 Rome, Italy

REFERENCES

1. Spencer TJ, Newcorn JH, Kratochvil CJ, Ruff D, Michelson D, Biederman J. Effects of atomoxetine on growth after 2-year treatment among pediatric patients with attention-deficit/ hyperactivity disorder. Pediatrics. 2005;116(1). Available at: www.pediatrics.org/cgi/content/full/116/1/e74

2. Poulton A. Growth on stimulant medication; clarifying the confusion: a review.Arch Dis Child.2005;90:801– 806

doi:10.1542/peds.2005-1895

In Reply.—

As we acknowledged in our article, potential differences in pubertal tempo may increase variability in the find-ings.1_{Although we did not know the pubertal staging for} individuals, it was a large sample, and we had no reason to think that the distribution of onset of puberty across the sample was likely to deviate markedly from the expected distribution. Moreover, this source of variabil-ity doesn’t invalidate the study findings. The only man-ner in which pubertal tempo would obscure adverse results would be if atomoxetine advanced pubertal tempo so that heightzscores seemed normal but growth terminated sooner than expected. There is no reason to believe that this occurred.

In our previous controlled studies of growth in boys and girls with and without attention-deficit/hyperactiv-ity disorder (ADHD), we used self-report to determine Tanner stages.2 _{Studies have shown that self-assessed} pubertal stages may be highly concordant with physi-cian-assessed pubertal staging.3 _{In neither study were} there differences between treated and untreated ADHD as well as control probands in the age of onset of esti-mated Tanner stages.2,4 _{In addition, in a separate,} 18-month relapse prevention study of atomoxetine that included a group randomly assigned to receive placebo after acute treatment, there was no evidence that atom-oxetine affected the onset of puberty during chronic treatment as assessed by comparisons between groups of (1) the number of patients in each group with a change

of at least 1 physician-assessed Tanner stage, (2) the mean time to first Tanner-stage change, and (3) the proportion of patients in each Tanner-stage group mov-ing to the next Tanner stage also found no affect on onset of pubertal stages.5

Despite the reassurance provided by these investiga-tions, we agree that longer studies are needed to fully understand growth issues in children with ADHD.

Thomas J. Spencer, MD Joseph Biederman, MD

Department of Psychiatry Massachusetts General Hospital Boston, MA 02114

Jeffrey H. Newcorn, MD

Department of Psychiatry Mount Sinai Medical Center New York, NY 10029

Christopher J. Kratochvil, MD

Department of Psychiatry University of Nebraska Medical Center Omaha, NE 68102

Dustin Ruff, PhD David Michelson, MD

Lilly Research Laboratories Indianapolis, IN 46285

REFERENCES

1. Spencer TJ, Newcorn JH, Kratochvil CJ, Ruff D, Michelson D, Biederman J. Effects of atomoxetine on growth after 2-year treatment among pediatric patients with attention-deficit/ hyperactivity disorder. Pediatrics. 2005;116(1). Available at: www.pediatrics.org/cgi/content/full/116/1/e74

2. Spencer TJ, Biederman J, Harding M, O’Donnell D, Faraone SV, Wilens TE. Growth deficits in ADHD children revisited: evidence for disorder-associated growth delays?J Am Acad Child Adolesc Psychiatry.1996;35:1460 –1469

3. Duke PM, Litt IF, Gross RT. Adolescents’ self-assessment of sexual maturation.Pediatrics.1980;66:918 –920

4. Biederman J, Faraone SV, Monuteaux MC, Plunkett EA, Gifford J, Spencer T. Growth deficits and attention-deficit/hyperactivity disorder revisited: impact of gender, development, and treat-ment.Pediatrics.2003;111:1010 –1016

5. Michelson D, Spencer T. Developmental outcomes of long-term atomoxetine treatment in ADHD [poster]. Presented at: Amer-ican Academy of Child and Adolescent Psychiatry annual meeting; October 19 –24, 2004; Washington, DC; p 98

doi:10.1542/peds.2005-2071

“Inferiority Complex” for a Reason

To the Editor.—

In their recentPediatricsarticle, Garcı´a Garcı´a et al1 con-clude that montelukast is not inferior to fluticasone in treating mild persistent asthma by using asthma rescue-free days (RFDs) as their primary objective in a 1-year study that involved 6- to 14-year-old patients despite the fact that patients on montelukast had significantly more

588 LETTERS TO THE EDITOR

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asthma attacks and required more rescue systemic and/or inhaled corticosteroids. Also, other secondary end points were significantly more improved in the flu-ticasone group (such as percentage of predicted forced expiratory volume in 1 second [FEV1], days with␤

-re-ceptor agonist use, and quality of life). The conclusion based on the primary end point (RFDs) is also doubtful. Although the authors calculated the noninferiority in-terval on the basis of prior studies and before recruit-ment, the results presented in their Table 2 for asthma RFDs clearly show that there is a statistically significant difference in the favor of fluticasone; the 95% confi-dence interval of mean difference between groups does not cross 0 (see also their results for FEV1 as percent

predicted for comparison).

Other problems concerning the study protocol and conclusions that the authors draw from the results are also apparent. There is ample of evidence from clinical studies that a different affect is seen with asthma therapy on different outcome measures including symptoms, lung function, exacerbations, need for short-acting bronchodilators, RFDs, and quality of life. Effectiveness of asthma therapy should be assessed by using appropri-ate outcome measures. The poor correlation between different outcome measures implies that⬎1 measure is required for the assessment of asthma control. Thus, if we find improved lung function, it does not mean that symptoms are resolved and exacerbations may still oc-cur.2 _{Thus, there is no simple outcome measure for} asthma, and there is a danger if we talk about effective-ness or equality of asthma therapy on the basis of only one end point (as in this case with asthma RFDs). On the other hand, there was robust evidence that fluticasone was more effective in controlling mild persistent asthma in children than montelukast (almost all outcome mea-sures were in favor of fluticasone).

The second problem was the recruitment criteria for mild persistent asthma. A recent study by Becharier et al3_{showed that the classification of severity of asthma in} children based on Global Initiative for Asthma guidelines (used in the Montelukast Study of Asthma in Children [MOSAIC] study) could lead to a serious mistake and include children from lower or higher severity catego-ries. Results of the study done by Zeiger et al4_{show that} in patients with the lower level of severity, fluticasone could not show its superiority because improvement of outcome measures reaches a plateau (the same for flu-ticasone and montelukast), showing noninferiority in that subgroup. Zeiger et al also found that RFDs im-proved similarly over the short-term, but with prolonged open-label treatment, asthma control improved more in the fluticasone-treated group. On the basis of their re-sults, they also conclude that classification criteria for mild persistent asthma may need to be reevaluated.

A number of approaches have been used to classify the severity of asthma. Following the Global Initiative

for Asthma guidelines, asthma severity is classified be-fore treatment is given on the basis of frequency of symptoms, medication use, and lung-function mea-sures.5_{According to the National Asthma Education and} Prevention Program’s guidelines for the diagnosis and management of asthma, asthma can be divided into 4 levels of severity: mild intermittent, mild persistent, moderate persistent, and severe persistent.6_The guide-lines provide criteria for classifying FEV1 (as percent

predicted) into 3 levels.5,6_{According to the results of the} Childhood Asthma Management Program Research Group, children with asthma may have a higher level of lung function than suggested in the guidelines’ classifi-cation scheme.7

Furthermore, pulmonary-function measures are not always consistent with levels of asthma severity. Isolated measures of lung function, especially FEV1, are of little

value in determining asthma severity, especially among patients who receive asthma-controller therapy3_{; on the} other hand, objective measures of lung function are essential in severity criteria of asthma. It is also well known that spirometric assessment of lung function is not always interpreted correctly, especially in younger children. The use of controller medications complicates the assignment of asthma severity.

Serious consequences may arise from the misclassifi-cation of asthma severity. Many patients who are con-sidered to have mild asthma may be undertreated, re-sulting inⱖ2 emergency-department visits per year that were required for 20% of patients with mild asthma.8 Undertreatment has an adverse impact on quality-ad-justed life-years, morbidity, mortality, and treatment costs. Also, it could have an important impact on the results of the MOSAIC study (recruitment bias) if more severe patients would be recruited in the montelukast group. This would allow montelukast to show greater improvement, and fluticasone would plateau. Because improvements in both groups were compared in the MOSAIC study, this could lead to noninferiority results for montelukast.

The third problem was the conclusion about the safety of fluticasone compared with montelukast in asth-matic children. The authors of the MOSAIC study con-clude that the patients in the fluticasone group had significantly lower (⫺0.41 cm) final height compared with those in the montelukast group even though this was not a planned comparison according to the pub-lished protocol. This conclusion is severely biased with the fact that groups were not of the same age span, there were more boys (64.8% vs 58.5%) in the montelukast group, and the age span also included adolescents in pubertal growth acceleration. Nothing is known about the actual sexual development status of the included patients between groups. Inclusion of more boys that reach higher final height and more subjects in the pu-bertal accelerated-growth phase could significantly bias

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the final result. Because the factors were not controlled and the randomization procedure was not planned to control for these factors that are very important for height velocity, no relevant conclusions could be made on the basis of the results of the MOSAIC study.

Mirjana Turkalj, MD, PhD

Department for Pulmonology and Allergology

Davor Plavec, MD, PhD

Department for Pulmonary Function Children’s Hospital Srebrnjak HR-10000 Zagreb, Croatia

REFERENCES

1. Garcı´a Garcı´a ML, Wahn U, Gilles L, Swern A, Tozzi CA, Polos P. Montelukast, compared with fluticasone, for control of asthma among 6- to 14-year-old patients with mild asthma: the MOSAIC study.Pediatrics.2005;116:360 –369

2. Chervinsky P, van As A, Bronsky EA, et al. Fluticasone propi-onate aerosol for the treatment of adult with mild to moderate asthma. The Fluticasone Propionate Asthma Study Group. J Allergy Clin Immunol.1994;94:676 – 683

3. Becharier LB, Strunk RC, Mauger D, White D, Lemanske RF, Sorkness CA. Classifying asthma severity in children: mismatch between symptoms, medication use, and lung function.Am J Respir Crit Care Med.2004;170:426 – 432

4. Zeiger RS, Bird SR, Kaplan MS, et al. Short-term and long-term asthma control in patients with mild persistent asthma receiving montelukast or fluticasone: a randomized controlled trial.Am J Med.2005;118:649 – 657

5. Global Initiative for Asthma.Global Strategy for Asthma Manage-ment and Prevention: NHLBI/WHO Workshop Report. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute; 2002. Publication 02-3659

6. Expert Panel Report 2.Guidelines for the Diagnosis and Manage-ment of Asthma. Bethesda, MD: National Heart, Lung, and Blood Institute, National Institute of Health; 1997. NIH Publication 97-4053

7. Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma.N Engl J Med.2000;343:1054 –1063

8. Taylor DM, Auble TE, Calhoun WJ, Mosesso VN Jr. Current outpatient management of asthma shows poor compliance with international consensus guidelines.Chest.1999;116:1638 –1645

doi:10.1542/peds.2005-2495

In Reply.—

The Montelukast Study of Asthma in Children (MOSAIC) clinical trial1_{is one of the first long-term (12 months of} treatment) and large (n ⫽ 994) studies comparing the relative benefit of an oral leukotriene-receptor antagonist (montelukast) and an inhaled corticosteroid (fluticasone) in asthma control in children. This was a noninferiority study of children with mild persistent asthma, with the percent asthma rescue-free days (RFDs) as the primary end point. This end point measures any day during which the patient did not use asthma rescue medication (such as an inhaled␤-agonist or an oral corticosteroid) and did not have an unscheduled visit to a physician, urgent/ emergency care, or hospitalization. This composite end point is a simple yet informative measure of the status of

the disease, assessing outcomes of relevance to the patient, as previously emphasized.2 _{Furthermore, such inclusive} end points may have advantages over “traditional” assess-ments of asthma control such as lung measures, given their frequent lack of reproducibility in young children and their lack of correlation with symptoms.

The results of the study showed that the mean differ-ence in percent RFDs between the 2 treatments was 2.8% (⬍1 day/month), an outcome that should not be clinically significant to patients. This result, of course, meets an essential condition of comparability of treat-ments in a noninferiority trial, namely, that the differ-ence between treatments be clinically nonimportant. However, several secondary end points favored flutica-sone.

The overlap in response distributions can often pro-vide a clearer determination of clinical comparability because the entire range of response of individuals in the study population is taken into account, which conveys to physicians a better understanding of the range of expectations for patient outcomes. In a posthoc, non-parametric analysis of the primary end point, there was a large degree of overlap (84.3% [95% confidence in-terval: 77.0 –91.6]) in the response of patients who were treated with either active therapy.

This was a randomized, double-blind study in which the baseline asthma characteristics between the 2 treat-ment groups were very similar. The growth results need to be confirmed further under additional controlled con-ditions, including Tanner stage of maturation. Along these lines, a recent 1-year, randomized, double-blind, placebo-controlled study of prepubertal children with mild persistent asthma showed that montelukast, in contrast to beclomethasone, did not affect linear growth.3

The management of asthma in children poses chal-lenges that differ from the treatment of asthma in adults. Current guidelines are inadequate: a case in point is the grouping of children⬎5 years old as adults in treatment recommendations and the lack of age-specific guidelines for children who are⬍5 years of age.4_Improved guide-lines are needed that encourage physicians to consider several therapeutic options for an optimal control of symptoms during the course of their long-term manage-ment of the child’s disease, taking into account issues of not just efficacy but also adherence, ease of use, and safety.

Marıá L. Garcıá Garcıá, MD

Hospital Severo Ochoa Leganes 28010 Madrid, Spain

REFERENCES

1. Garcı´a Garcı´a ML, Wahn U, Gilles L, Swern A, Tozzi CA, Polos P. Montelukast, compared with fluticasone, for control of asthma among 6- to 14-year-old patients with mild asthma: the MOSAIC study.Pediatrics.2005;116:360 –369

590 LETTERS TO THE EDITOR

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DOI: 10.1542/peds.2005-2495

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''Inferiority Complex'' for a Reason

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