1104 • CID 2007:45 (15 October) • CORRESPONDENCE 15 OCTOBER Correspondence Oral Pentoxifylline and Pentavalent Antimony for Treatment of Leishmaniasis: Promising but Inconclusive Evidence of Superiority, Compared with Antimony Monotherapy To the Editor—Machado et al. [1] re- cently reported the results of a double- blind, placebo-controlled, randomized clinical trial that compared the effective- ness of pentoxifylline and antimony dual therapy with that of antimony monother- apy in patients with mucosal leishmani- asis. The authors concluded that dual ther- apy reduced healing time and was superior to antimony monotherapy for leishman- iasis eradication. However, the results should be interpreted cautiously. Critical methodologic limitations warrant atten- tion to foster appropriate clinical in- terpretation. The study by Machado et al. [1] illus- trates the inability of small-sample ran- domization to allocate groups with com- parable baseline risks for the outcome. Participation was limited to 23 partici- pants overall—11 participants in the in- tervention group and 12 participants in the control group. Randomization of small study populations may introduce accidental bias from failure to maintain equal distribution of confounders between comparison groups, regardless of statisti- cal significance [2]. Machado et al. [1] re- ported a lack of statistically significant dif- ferences between the 2 groups. However, the study was insufficiently powered to observe statistically significant differences, and the observed clinically relevant dif- ferences between groups suggest the in- troduction of bias. Previous studies have reported that older age, male sex, longer duration of symptoms, and previous cu- taneous leishmaniasis may be related to risk of mucosal leishmaniasis, disease se- verity, and time to cure [3, 4]. The anti- mony plus placebo group was older and had a greater proportion of male partic- ipants, longer duration of symptoms, and greater frequency of cutaneous leishman- iasis, compared with the antimony plus pentoxifylline group; these findings indi- cate that the pentoxifylline group had a greater probability for eradication at base- line than did the placebo group. Conse- quently, a greater probability of cure in the group who received dual therapy, compared with the group who received monotherapy, may have created a positive bias away from the null (i.e., overestimated the effectiveness of dual therapy). Acci- dental bias offers a plausible alternative explanation for the authors’ findings, em- phasizes the inadequacy of hypothesis test- ing to evaluate the comparability of small groups [5, 6], and underscores the neces- sity for a larger randomized trial. It is unclear why Machado et al. [1] did not provide an effect estimate, such as risk difference or hazard ratio, using robust statistical techniques for small trials [7]. The failure to report an effect estimate un- dermines comparison. Furthermore, effect estimates facilitate cost-effectiveness eval- uations, which are particularly important for resource-limited regions where leish- maniasis commonly occurs. Effect esti- mates with corresponding confidence in- tervals for the outcome would have more appropriately elucidated the potential clin- ical use of dual therapy. The small sample size used by Machado et al. [1] greatly limited potential infer- ences because of the failure to produce comparable groups after randomization and compromised statistical testing. Therefore, the study may not constitute decisive evidence for the superiority of pentoxifylline and antimony dual therapy for mucosal leishmaniasis. Future studies should recognize the limitations of hy- pothesis testing and P values to evaluate whether small groups are comparable after randomization [5, 6]. Ultimately, small sample sizes may lead to inconclusive in- ferences and warrant conservative inter- pretations from a clinical perspective until further evidence is available. Acknowledgments Potential conflicts of interest. All authors: no conflicts. Rohit P. Ojha, Diana Cervantes, and Lori A. Fischbach Department of Epidemiology, University of North Texas Health Science Center, Fort Worth, Texas References 1. Machado PR, Lessa H, Lessa M, et al. Oral pentoxifylline combined with pentavalent an- timony: a randomized trial for mucosal leish- maniasis. Clin Infect Dis 2007; 44:788–93. 2. Friedman LM, Furberg CD, DeMets DL. Fun- damentals of clinical trials. 3rd ed. New York: Springer Science, 1998:61. 3. Castellucci L, Cheng LH, Araujo C, et al. Fa- milial aggregation of mucosal leishmaniasis in northeast Brazil. Am J Trop Med Hyg 2005; 73: 69–73. 4. Machado-Coelho GL, Caiaffa WT, Genaro O, Magalhaes PA, Mayrink W. Risk factors for mu- cosal manifestation of American cutaneous leishmaniasis. Trans R Soc Trop Med Hyg 2005; 99:55–61. 5. Kernan WN, Viscoli CM, Makuch RW, Brass LM, Horwitz RI. Stratified randomization for clinical trials. J Clin Epidemiol 1999; 52:19–26. 6. Scales DC, Rubenfeld GD. Estimating sample size in critical care clinical trials. J Crit Care 2005; 20:6–11. 7. Evans CH, Ildstad ST. Small clinical trials: issues and challenges. Washington, DC: National Academy Press, 2001:60–90. Reprints or correspondence: Rohit P. Ojha, Dept. of Epide- miology, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., CBH Ste. 355, Fort Worth, TX 76107 (rojha@hsc.unt.edu). Clinical Infectious Diseases 2007; 45:1104  2007 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2007/4508-0028$15.00 DOI: 10.1086/523592 Downloaded from https://academic.oup.com/cid/article/45/8/1104/346847 by guest on 05 July 2021