|
Title: Problems in the
Design and Reporting of Trials of Antifungal Source: JAMA, The Journal of
the American Medical Association, Nov 10, InfoTrac Web: Health Reference Center-Academic.
|
|
Abstract: All medical researchers should keep copies of their data when conducting clinical trials. This will ensure that other researchers will have complete data when and if they use those trials in meta-analyses. Meta-analysis is a technique used to combine the results of many different clinical trials into one large trial. However, many of the individual trials may have used different techniques or different methods. Researchers who conducted a meta-analysis of antifungal drugs used to treat cancer patients discuss the various problems that may arise. Subjects: Meta-analysis - Evaluation Antifungal agents - Evaluation Electronic Collection: A57604445 RN: A57604445 Full Text COPYRIGHT 1999 American Medical Association Meta-analyses may become biased if the reported data in the individual trials are biased and if overlap among trials cannot be identified. We describe the unanticipated problems we encountered in collecting data for a meta-analysis comparing a new antifungal agent, fluconazole, with amphotericin B in patients with cancer complicated by neutropenia. In 3 large trials that comprised 43% of the patients identified for the meta-analysis, results for amphotericin B were combined with results for nystatin in a "polyene" group. Because nystatin is recognized as an ineffective drug in these circumstances, this approach creates a bias in favor of fluconazole. Furthermore, 79% of the patients were randomized to receive oral amphotericin B, which is poorly absorbed and not an established treatment, in contrast to intravenous amphotericin B, which was administered in 4 of 5 placebo-controlled trials, or 86% of patients. It was unclear whether there was overlap among the "polyene" trials, and it is possible that results from single-center trials were included in multicenter trial reports. We were unable to obtain information to clarify these issues from the trial authors or the manufacturer of fluconazole. Two of 11 responding authors replied that the data were with the drug manufacturer and two indicated that they did not have access to their data because of change of affiliation. In the meta-analyses, fluconazole and amphotericin B (mostly given orally) had similar effects (13 trials), whereas nystatin was no better than placebo (3 trials). Since individual trials are rarely conclusive, investigators, institutions, and pharmaceutical companies should provide essential details about their work to ensure that meta-analyses can accurately reflect the studies conducted and that patients will realize maximum benefits from treatments. We recommend that investigators keep copies of their trial data to help facilitate accurate and unbiased meta-analyses. META-ANALYSES MAY become biased if the data in the individual trials are reported in a biased fashion and if authors and companies are not explicit about multiple publications of the same data. Problems with unclear reporting of trial data were recently described for the antipsychotic drug risperidone [1] (manufactured by Janssen Pharmaceutica NV, Beerse, Belgium) and have been noted earlier, including instances of reports of the same trial with no common authors. [2,3] We have reported previously a meta-analysis of placebo-controlled trials of antifungal agents in patients with cancer complicated by neutropenia. [4,5] We report herein briefly a meta-analysis of trials that compared the 2 most effective drugs, fluconazole and amphotericin B. The main focus of this article is not the meta-analysis, which will be described in detail elsewhere, [6] but the unanticipated problems we encountered in its conduct. Fluconazole is a new antifungal agent (manufactured by Pfizer Inc, New York, NY). Fluconazole is well absorbed after oral intake and is used both orally and intravenously. In contrast, amphotericin B (manufactured by Bristol-Myers Squibb, New York, NY) is poorly absorbed and is not recommended for oral use. [7] Although most fungal infections enter the body through the gastrointestinal tract and oral amphotericin B eliminates fungi from the gastrointestinal tract in the majority of patients, [8,9] there is little documentation of its clinical effect when given orally. Chemically, amphotericin B is a polyene and thus belongs to the same class of drugs as nystatin. Nystatin (manufactured by Bristol-Myers Squibb, New York, NY) is almost insoluble, is considered to be a poor drug for treatment of patients with immunodeficiency, and is not recommended for use in cancer patients with neutropenia. [7] Hence, we were surprised to find that most trials that compared fluconazole with amphotericin B had used oral, and not intravenous, amphotericin B and that some of the results for this drug had been combined with the results for nystatin. METHODS The primary aim of the meta-analysis was to compare the effect of fluconazole and amphotericin B on total mortality in patients with cancer complicated by neutropenia. Secondary outcomes included invasive fungal infection, colonization, need for additional (rescue) antifungal treatment, and adverse effects leading to discontinuation of therapy. Search Strategy All randomized trials, irrespective of language, that compared fluconazole with amphotericin B in cancer patients with neutropenia were eligible. Letters, abstracts, and unpublished trials were also reviewed to reduce the influence of publication bias. We excluded studies that concerned solely prevention or treatment of oral candidiasis. As described previously,[4,5] we performed a comprehensive MEDLINE search from 1966 on, most recently updated in March 1998. Information about trials not registered in MEDLINE, including those unpublished, were located by contacting the manufacturers and the authors and by scanning reference lists of articles and reviews. We also scanned selected conference proceedings and searched the Cochrane Library. [5,6] Three of the reports we retrieved described large, 3-armed trials that had compared fluconazole, amphotericin B, and nystatin but had combined the outcomes for amphotericin B and nystatin in a "polyene" group. Since these trials comprised 43% of the total patients in our meta-analysis, we did not wish to exclude them. Instead, we estimated the effect of amphotericin B in the polyene trials based on findings of an additional meta-analysis of trials comparing nystatin with placebo, fluconazole, or amphotericin B. We repeated the search strategy, adding nystatin to the list of drugs. Since we suspected there would be few trials of nystatin in cancer patients with neutropenia, [7] we included all severe diseases predisposing to fungal infection. Data Extraction Details on diagnosis, drugs administered, dosage, length of follow-up, randomization and blinding methods, number of randomized patients, number of patients excluded from analysis, deaths, invasive fungal infections, colonization, use of additional (rescue) antifungal therapy, total number of dropouts, and dropouts due to adverse effects were extracted by each of us independently. We defined invasive fungal infection as a positive blood culture, esophageal candidiasis, lung infection, or microscopically confirmed deep tissue infection. [4,5] Disagreements were resolved by discussion. We used MEDLINE and abstract books to obtain the authors' most recent addresses. All authors were asked to confirm the extracted information and to answer additional questions. We specifically asked for mortality data 3 months after study entry for all patients, including those the authors had excluded after the randomization. We also sought details on the randomization process, especially whether treatment allocation was concealed (eg, central randomization, sealed envelopes, or a code provided by a pharmacy or a company). Since the response rate to our requests for additional information on the fluconazole trials was low, we did not contact the authors for the meta-analysis of nystatin. Statistical Analysis The outcomes were weighted by the inverse variance of the log odds ratio. A fixed-effects analysis was performed if P[greater than].10 for the test of heterogeneity; otherwise, a random-effects analysis was made. [10] The Cochrane Collaboration's statistical software was used [11]; odds ratios and 95% confidence intervals (CIs) are presented. RESULTS Searches for Trials Comparing Fluconazole With Amphotericin B Our searches initially indicated that 18 relevant trials had been performed. [8,12-28] We excluded a trial in which only 22 of the 41 patients had been randomized, [22] and another that was recently published as an abstract: it described 310 patients but did not report any outcome data. [27] We excluded a third report [23] because its results were included in a multicenter study report. [19] We mailed letters to the remaining 15 authors, requesting one of them to confirm whether his trial report [25] was included in a multicenter study report [19] and the others to check a list of data we had extracted from their study for accuracy and to inform us whether the randomization process had been concealed, whether they possessed mortality data after 3 months, and whether they were aware of any unpublished trials. Authors of trial reports of oral amphotericin were asked why they had not used intravenous amphotericin, and authors of polyene trial reports were asked why they had not reported the results for amphotericin and nystatin separately, since these drugs were not equally effective. In addition, the authors were asked to clarify uncertainties related specifically to their studies. The responses to our requests for confirmation of the extracted data and for supplementary information are shown in the TABLE. Two authors from Japan [12,24] responded to our first letter. After a second round of letters, we obtained answers to some of our questions from a third author. [14] We contacted 3 authors in person at meetings and 1 by telephone. This led to an answer from a fourth author. [21] One author, Marie, whose trial we identified because it was briefly mentioned in a conference abstract by Viscoli [26], wrote in response to our question as to whether the study had been published that his trial was old and that the data were with the drug manufacturer. However, the trial was actually published, which we discovered when we wrote to the author of another conference abstract, [28] Lapierre, who sent an extensive manuscript in English and a full publication in French from 1993 [29] that was not indexed by MEDLINE. This report had Marie as first author and Lapierre as second author. Thus, the 2 abstracts referred to the same trial. One author, who was a Pfizer associate, did not respond. [5] When we contacted Pfizer Central Research in the United Kingdom by letter and telephone, the responding person informed us that he was unable to devote the time required to do the work, and indicated that he passed on our request to colleagues in New York. One author answered 2 questions by memory and responded that the university at which he was previously employed had refused to give him a copy of his studies. [13] Of the remaining 7 authors (Table), 3 did not respond [16,18,25] another noted that she did not have access to the databases because of change of affiliation [8]; 1 indicated that she would send the full report when it was published [20]; 1 indicated that he would contact the company where the data were on file [19]; and 1 indicated that he would try to find the data.[17] Problems With Overlap of Polyene Trials In 3 large trials, [15,18,19] the patients were randomized to 3 arms: fluconazole, amphotericin B, or nystatin. However, as noted above, the results of these trials were not reported per treatment group, but were reported as if the studies had been 2-armed, comparing fluconazole with a polyene group. The relationships between the trials and the centers contributing to them were unclear. One of the trials was reported as a multicenter study of 536 patients with Philpott-Howard as first author. [19] The trial report described that patients taking amphotericin B received 2 g/d and that the results from 50 patients at 1 of the centers had been published previously. However, these patients had received 1600 mg/d. [23] Furthermore, a third report by Finke described 40 patients who received 800 mg/d. [25] In that article, [25] Finke noted that his study was part of a multicenter trial and referenced an abstract that had Brammer, identified as a Pfizer employee, as coauthor. Brammer also coauthored the report by Philpott-Howard, [19] which had not included Finke among the authors and did not reference his trial report, but it mentioned Finke as a member of the Multicentre Study Group. We therefore excluded Finke's trial, assuming it was a duplicate publication. A fourth trial report of 248 patients who received "at least 2 g daily" listed Brammer as the only author. [15] This report was an interim analysis but it was not referenced by newer reports. Since its methodology is very similar to that of the other trials and several of the investigators were the same as in Philpott-Howard's report, we suspected the study by Brammer [15] might represent partial overlap of contributing centers or possibly duplicate publication. Because of the uncertainty, we included the report [15] in our meta-analysis (exclusion of the report would make a trivial difference). The fifth polyene trial report seemed to describe a unique study by Ninane et al, [18] but it nevertheless reported that patients at 1 of the centers had received amphotericin B and nystatin simultaneously, rather than in separate treatment arms. Furthermore, a recent publication, identified after the cut-off for our search, [30] described a trial of 50 patients who were randomized to receive fluconazole or nystatin. This trial was 2-armed even though the article mentioned that 18 patients "were in part included in a previously reported multicentre study." This study was the 3-armed study by Ninane et al. [18] These findings raise the question of whether some single-center trials had not originally been part of a multicenter trial, but had been combined in the polyene multicenter trial reports. Results of the Meta-analyses The meta-analysis of the nystatin trials showed that the effect of this drug is similar to that of placebo (APPENDIX). Therefore, to provide a reasonable range for the estimates of the effect of amphotericin B in the 3-armed polyene studies, we performed 2 sets of analyses. In one, we used the data as reported (unadjusted analysis) while in the other, we assumed that nystatin and placebo had the same effect (adjusted analysis). Since the combined polyene group and the fluconazole group were of very similar size in all 3 studies, we assumed that equal numbers of subjects had been randomized to receive amphotericin B and nystatin. For the adjustments, we used the relative risks for amphotericin B vs placebo that we found in our previous meta-analysis [4,5]: 0.41 for invasive infection. Therefore, we would expect 41 infections in patients receiving amphotericin B for every 100 infections in patients receiving nystatin; ie, the expected fraction of infections for amphotericin B in the polyene trials is 41/141 = 0.29. Thus, for a study that reported 7 infections in the polyene group, [19] the expected number of infections in the amphotericin B subgroup would be 7 X 0.29 = 2.0. Doubling this number equals 4 infections for patients receiving amphotericin B, which is what we would have expected to find if all patients receiving polyenes had received this drug. After the exclusions explained above, 13 trials were left for the meta-analysis of fluconazole vs amphotericin B. The antifungal agent was given prophylactically in 8 trials, [8,12,14,15,17-19,24] empirically in 4, [13,20,21,26] and as treatment in 1. [16] The most common diseases were acute leukemia in 9 trials [8,12,14,15,17-20,26] bone marrow transplantation in 2, [21,24] other cancers in 1, [13] and cancer with esophageal candidiasis in 1. [16] Treatment allocation was adequately concealed in 6 trials [12-14,21,24,26]; none of the trials were blinded. The total number of patients was 2977. The trial drugs were given intravenously to 628 patients (21%) and orally to the remaining patients (79%). The effect estimates of the trials and the full results of the meta-analysis will be published in the Cochrane Library [6]; a brief summary follows below. Deaths. The mortality was similar in prophylactic and empirical studies. When oral fluconazole was compared with oral polyenes, the odds ratio was 0.64 (95% CI, 0.33-1.23) in the unadjusted analysis and 0.82 (95% CI, 0.411.64) in the adjusted analysis. The summary odds ratio estimate for all the trials was 0.83 (95% CI, 0.62-1.11) in the unadjusted analysis and 0.87 (95% CI, 0.65-1.17) in the adjusted analysis. Invasive Fungal Infection. When oral fluconazole was compared with oral polyenes, the odds ratio was 0.66 (95% CI, 0.27-1.60) in the unadjusted analysis and 1.14 (95% CI, 0.41-3.16) in the adjusted analysis. The summary odds ratio estimate for all the trials was 0.87 (95% CI, 0.60-1.27) in the unadjusted analysis and 0.96 (95% CI, 0.65-1.40) in the adjusted analysis. Colonization. No adjustments were necessary for the polyene studies because they did not report data on colonization. The summary odds ratio estimate for all the trials was 0.92 (95% CI, 0.54-1.55). COMMENT We experienced unexpected difficulties in obtaining responses to our requests for additional or clarifying information about studies of antifungal agents. Although we asked the authors to answer only those questions they could and all the studies had been published between 1990 and 1996, we received additional data from only 3 of the 15 authors after 2 letters. In contrast, 9 of 13 authors of reports published in the 1990s provided additional information for our previous meta-analysis of the placebo-controlled trials [4,5] (P = .02 for the difference in response rate). Support from the manufacturer of fluconazole (Pfizer, Inc) was specifically mentioned in 9 of the trial reports and in a single-center version [30] of an additional trial [18] (Table), corresponding to 92% of the patients in these studies included in the meta-analysis. No sources of support from industry or public sources were listed for the other 3 trials. Two of the authors indicated that the data were with the company and 2 indicated that they did not have access to their own data because of change of affiliation. Hence, we suggest that trial investigators should keep copies of their study data. The majority of the control patients were given oral amphotericin B, which is poorly absorbed [7] and poorly documented. [4,5,7] None of the 7 trial reports using oral administration offered a rationale for this decision. These trials comprised 79% of the randomized patients, which is in contrast to the placebo-controlled trials of amphotericin B in which intravenous drug was given in 4 out of 5 studies, corresponding to 86% of the patients. [4,5] This difference probably could not be explained by trends in approach or setting because 2 of the trials of intravenous amphotericin B were from the same period as those of oral administration and also concerned prophylaxis. We find it remarkable that the rationale for combining the results for amphotericin B and nystatin in a polyene group was not explained in any of the reports of the 3-armed trials. The relation between these trials and the boundaries between them were obscure. For example, the dosage of amphotericin B was not the same in various publications of the same trial. Furthermore, data from a 2-armed trial [30] were used in a report of a 3-armed trial, [18] which suggests that patients in the 3-armed trial may not have been truly randomized to 3 arms, although the trial was described as such. When the trials were planned and conducted, nystatin was recognized as being an ineffective drug for invasive fungal infection. [7,15] For example, Brammer, the author of 1 of the polyene reports [15] that was also the first published comparison of fluconazole and amphotericin B, wrote that "there has been no convincing evidence to demonstrate that [oral preparations of nystatin and amphotericin B] reduce the incidence of systemic invasion by Candida yeasts." [15] We believe we have shown that the polyene trials are biased in favor of fluconazole. First, nystatin is no better than placebo when given to patients with severe immunodeficiency, such as those with cancer complicated by neutropenia (Appendix). Second, the difference between fluconazole and nystatin, odds ratio 0.27 for fungal infection and 0.19 for colonization (0.40 if the 2 treatment trials are excluded [Appendix]), is similar to the difference between fluconazole and placebo, which we have reported previously (0.38 and 0.31, respectively). [5] Another indication that oral amphotericin B and nystatin are not the same is shown by the number of dropouts due to adverse effects. More patients dropped out while taking oral amphotericin B than fluconazole, whereas the opposite was noted for oral polyenes, and the difference between the 2 odds ratios is significant (P = .002, normal approximation) (details to be published in the Cochrane Library [6]). The effect of our adjustments for this bias was seen most clearly for invasive fungal infection, which was the only variable for which there were data from all three 3-armed trials. The odds ratio changed from 0.66 to 1.14 after the adjustments, which is in better agreement with the effect noted in the other studies [8,12,17,24] that had compared oral drugs (odds ratio, 1.02). However, the bias could be more pronounced than what we found. For example, in a similar meta-analysis recently presented at an international congress, [31] azoles (mainly fluconazole) were reported to be considerably and significantly better than polyenes, with odds ratios of 0.59 (95% CI, 0.40-0.87) for reducing superficial fungal infection and 0.44(95% CI, 0.27-0.71) for reducing definite invasive infection. This meta-analysis had a Pfizer associate among the authors, so it would have been possible to report the results for amphotericin B separately. Another example of discrepant meta-analyses has been encountered for the selective serotonin reuptake inhibitor fluoxetine (Prozac, Eli Lilly and Company, Indianapolis, Ind). A similar dropout rate for this drug as for tricyclic antidepressants (P = .40) was reported in i meta-analysis, [32,33] whereas a second meta-analysis, published as a correspondence by a company employee in response to the first meta-analysis, found a marked difference in favor of fluoxetine (P[less than].001]). [34] However, the second meta-analysis contained fewer patients than the first, had less power, and included unpublished "data on file," which are usually less favorable for new treatments than published ones. [35,36] As illustrated by this example and by our own meta-analysis, we believe readers should be skeptical about meta-analyses that contain unpublished data to which only the sponsor has access. Such experiences may create mixed feelings for the patients and may detract from their willingness to volunteer for clinical trials. Study subjects of ten participate in clinical research for the benefit of future patients and they have a right to expect that the results can be trusted and openly discussed. Since individual trials are rarely conclusive, we suggest that it would be valuable for patients if investigators, institutions, and pharmaceutical companies were more helpful to those conducting meta-analyses. Editor's Nate: JAMA contacted Pfizer Inc (New York, NY) by mail and telephone to solicit a response to be published concurrently with this article. This offer was declined. Author Contributions: Dr Johansen wrote the draft of the meta-analysis protocol. Drs Johansen and Getzsche contributed equally to trial selection, data extraction, and writing the manuscript. Both are guarantors of this article. Funding/Support: This study was supported by grants from JASCHA-fonden, H:S Rigshospitalet, Nordic Council of Ministers, and Sygekassernes Helsefond, Copenhagen, Denmark; and The Swedish Society of Medicine, Stockholm. Acknowledgment: We thank the following investigators for additional information on their trials: Hideki Akiyama, MD; Gerald B. Bodey, MD; V. Lapierre, MD; H. Teshima, and Claudio Viscoli, MD. We are grateful for the translation of the Japanese article provided by Hiroto Takada and assistance from the German Cochrane Centre in locating German authors. Author Affiliations: The Nordic Cochrane Centre, Rigshospitalet, Copenhagen, Denmark. Corresponding Author: Peter C. Gotzsche, MD, DMSc, The Nordic Cochrane Centre, Rigshospitalet, Department 7112, DK-2100 Copenhagen O, Denmark (e-mail: p.c.gotzsche@cochrane.dk). REFERENCES (1.) Huston P, Moher D. Redundancy, disaggregation, and the integrity of medical research. Lancet. 1996;347:1024-1026. (2.) Gotzsche PC. Multiple publication of reports of drug trials. Eur J Clin Pharmacol. 1989;36:429-432. (3.) Tramer MR, Reynolds DJ, Moore RA, McOuay HJ. Impact of covert duplicate publication on meta-analysis: a case study. BMJ. 1997;315:635-640. (4.) Gotzsche PC, Johansen HK. Meta-analysis of prophylactic or empirical antifungal treatment versus placebo or no treatment in patients with cancer complicated by neutropenia. BMJ. 1997;314:1238-1244. (5.) Gotzsche PC, Johansen HK. Meta-analysis of prophylactic or empiric antifungal therapy vs placebo or no treatment in cancer patients with neutropenia [Cochrane Review on CD-ROM]. Oxford, England: Cochrane Library, Update Software; 1998: issue 1. (6.) Johansen HK, Gotzsche PC. Amphotericin B vs fluconazole in neutropenic cancer patients [protocol for Cochrane Review]. Oxford, England: Cochrane Library, Update Software; 1998: issue 3. (7.) Working Party of the British Society for Antimicrobial Chemotherapy. Chemoprophylaxis for candidosis and aspergillosis in neutropenia and transplantation: a review and recommendations. J Antimicrob Chemother. 1995;36:899-909. (8.) Meunier F, Aoun M, Janssens M, Dekoster C, Paesmans M. Chemoprophylaxis of fungal infections in granulocytopenic patients using fluconazole vs oral amphotericin B. Drug Invest. 1991;3:258-265. (9.) Bodey GP, Rosenbaum B. Effect of prophylactic measures on the microbial flora of patients in protected environment units. Medicine (Baltimore). 1974;53:209-228. (10.) DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177-188. (11.) Review Manager (RevMan) [computer program]. Version 3.1 for Windows. Oxford, England: The Cochrane Collaboration; 1998. Available at: http:// www.cochrane.dk. (12.) Akiyama H, Mori S, Tanikawa S, Sakamaki H, Onozawa Y. Fluconazole versus oral amphotericin B in preventing fungal infection in chemotherapy-induced neutropenic patients with haematological malignancies. Mycoses. 1993;36:373-378. (13.) Anaissie EJ, Darouiche RO, Abi-Said D, et al. Management of invasive candidal infections: results of a prospective, randomized, multicenter study of fluconazole versus amphotenicin B and review of the literature. Clin Infect Dis. 1996;23:964-972. (14.) Bodey GP, Anaissie EJ, Elting LS, Estey E, O'Brien S, Kantarjian H. Antifungal prophylaxis during remission induction therapy for acute leukemia fluconazole versus intravenous amphotenicin B. Cancer. 1994;73:2099-2106. (15.) Brammer KW. Management of fungal infection in neutropenic patients with fluconazole. Hamatol Bluttransfus. 1990;33:546-550. (16.) Lake DE, Kunzweiler J, Beer M, Buell DN, Islam MZ. Fluconazole versus amphotericin B in the treatment of esophageal candidiasis in cancer patients. Chemotherapy. 1996;42:308-314. (17.) Menichetti F, Del Favero A, Martino P, et al. Preventing fungal infection in neutropenic patients with acute leukemia: fluconazole compared with oral amphotericin B. Ann Intern Med. 1994;120:913-918. (18.) Ninane J, for the Multicentre Study Group. A multicentre study of fluconazole versus oral polyenes in the prevention of fungal infection in children with hematological or oncological malignancies. Eur J Clin Microbiol Infect Dig. 1994;13:330-337. (19.) Philpott-Howard JN, Wade JJ, Mufti GJ, Brainmer KW, Ehninger G, for the Multicentre Study Group. Randomized comparison of oral Fluconazole versus oral polyenes for the prevention of fungal infection in patients at risk of neutropenia. J Antimicrob Chemother. 1993;31:973-984. (20.) Silling-Engelhardt G, Fegeler W, Roos N, Schomaker R, Essink M, Buchner T. Early empiric antifungal treatment of infections in neutropenic patients comparing fluconazole with amphotericin B/5-flucytosine. Blood. 1994;10(suppl 1):306a. (21.) Viscoli C, Castagnola E, Van Lint MT, et al. Fluconazole versus amphotericin B as empirical antifungal therapy of unexplained fever in granulocytopenic cancer patients: a pragmatic, multicentre, prospective and randomised clinical trial. Eur J Cancer. 1996;32A:814-820. (22.) Ellis ME, Halim MA, Spence D, et al. Systemic amphotericin B versus fluconazole in the management of antibiotic resistant neutropenic fever: preliminary observations from a pilot, exploratory study. J Infect. 1995;30:141-146. (23.) Rozenberg-Arska M, Dekker AW, Branger J, Verhoef J. A randomized study to compare oral fluconazole to amphotericin B in the prevention of fungal infections in patients with acute leukaemia. J Antimicrob Chemother. 1991;27:369-376. (24.) Teshima H, Masaoka T, Hiraoka A, et al. A randomised study to compare oral fluconazole with oral amphotericin B for suppression of fungal flora and prevention of fungal infection in bone marrow transplantation recipients. Drug Evaluation. 1994;7:535-542. (25.) Finke R. Comparison of oral fluconazole and amphotericin B prophylaxis against fungal infections in the neutropenic phase of patients treated with antileukemic agents [in German]. Mycoses. 1990;33 (suppl 1):42-54. (26.) Viscoli C. European studies of fluconazole (F) vs amphotericin B (AmB) in febrile neutropenic cancer patients. In: Program and abstracts of the Seventh European Congress of Clinical Microbiology and Infectious Diseases; March 26-30, 1995; Vienna, Austria. Abstract 70. (27.) Winston DJ, Hathorn J, Schuster M. Fluconazole versus amphotericin B for empiric antifungal therapy of febrile neutropenic patients: results of a randomised multicenter trial. In: Program and abstracts of the 20th International Congress of Chemotherapy; June 29-July 3, 1997; Sydney, Australia. Abstract 3243. (28.) Lapierre V, Marie J-P, Pico JL, et al. Intravenous fluconazole (Flu) versus intravenous amphotericin B (AmB) in the management of febrile neutropenic patients: a multicentric randomized study. In: Program and abstracts of the 32nd Interscience Conference on Antimicrobial Agents and Chemotherapy; October 1992; Anaheim, Calif. Abstract 624. (29.) Marie J-P, Lapierre V. Pico J, et al. Etude multicentrique randomisee fluconazole iv versus amphotericine B iv chez le patient neutropenique et febrile. Cah Onchol. 1993;2:171-173. (30.) Groll AH, Just-Nuebling G, Kurz M, et al. Fluconazole versus nystatin in the prevention of candida infections in children and adolescents undergoing remission induction or consolidation chemotherapy for cancer. J Antimicrob Chemother. 1997;40:855-862. (31.) Bow EJ, Laverdiere M, Lussier N, Rotstein C, loannou S. Anti-fungal prophylaxis in neutropenic cancer patients: a meta-analysis. In: Program and abstracts of the 37th lnterscience Conference on Antimicrobial Agents and Chemotherapy; September 28-October 1, 1997; Toronto, Ontario. Abstract LM-88. (32.) Song F, Freemantle N, Sheldon TA, et al. Selective serotonin reuptake inhibitors: meta-analysis of efficacy and acceptability. BMJ. 1993;306:683-687. (33.) Smith GD, Egger M. Unresolved issues and future developments. BMJ. 1998;316:221-225. (34.) Nakielny J. Effective and acceptable treatment for depression [letter]. BMJ. 1993;306:1125. (35.) Stern JM, Simes JR. Publication bias: evidence of delayed publication in a cohort study of clinical research projects. BMJ. 1997;315:640-645. (36.) Hemminki E. Study of information submitted by drug companies to licensing authorities. BMJ. 1980; 280:833-836. Contacts With Authors and Sponsoring Company and Outcomes [*] Author and/or Employee Means of Contact Anaissie et al, [13] 1996 3 Letters, personal contact at the 1997 Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting, fourth letter, e-mail message Bodey et al, [14] 1994 2 Letters Lake et al, [16] 1996 2 Letters Marie et al, [29] 1993 1 Letter Lapierre et al, [28] 1992 3 Letters Silling-Engelhardt 1 Letter, letter to editor-in-chief of et al, [20] 1994 Blood, letter to publishers (the American Society of Hematology), letter to the German Cochrane Centre, final letter to author Viscoli et al, [21] 1996, 2 Letters, personal contact at Viscoli et al, [26] 1995 1997 European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) Akiyama et al, [12] 1993 1 Letter Menichetti et al, [17] 1994 2 Letters, personal contact at the 1997 ICAAC meeting Meunier et al, [8] 1991 2 Letters Teshima et al, [24] 1994 1 Letter Finke, [25] 1990 2 Letters, letter to the German Medical Association, letter to the German Cochrane Centre Brammer, [15] 1990 2 Letters Ninane et al, [18] 1994 3 Letters Philpott-Howard 2 Letters, 3 telephone calls et al, [19] 1993 Troke (Pfizer Central 1 Letter, 1 telephone call Research, Sandwich, England) Author and/or Employee Outcome Anaissie et al, [13] 1996 3 Letters returned because of unknown address; reply to fourth letter: "I do not have access to the data (they are in the possession of the University of Texas, MD Anderson Cancer Center). I will make a request based on your letter and hope to receive a copy." Answer to e-mail message: "I am unable to provide you with data because the institution I was at has refused to give me a copy of my studies." Bodey et al, [14] 1994 Answer to second letter Lake et al, [16] 1996 No answer Marie et al, [29] 1993 Answer: "It is an old trial, and all the data are with Pfizer." Lapierre et al, [28] 1992 Answer to third letter (which had a more detailed address); sent a copy of a full article in French and a draft manuscript in English Silling-Engelhardt The letter was returned because of unknown address. et al, [20] 1994 The response from Blood said, "We do not have an address for the authors of the abstract." No answer from publishers. The German Cochrane Centre identified the author who had changed her name to Silling. Answer to final letter: "I am waiting for an answer, whether it will be accepted ... The published data will answer nearly all of your questions." Viscoli et al, [21] 1996, No answer to letters; answer obtained after personal Viscoli et al, [26] 1995 contact Akiyama et al, [12] 1993 Answer to first letter Menichetti et al, [17] 1994 No answer to letters; at the personal contact, the author indicated that he would try to find the data; no answer Meunier et al, [8] 1991 Answer to second letter: "Unfortunately, due to various reasons including my change of affiliation since 1991, I do not have access to the databases requested." Teshima et al, [24] 1994 Answer to first letter Finke, [25] 1990 No answer to letters; unknown to Deutsche Arzte Verlag; new address obtained from the German Cochrane Centre; the third letter was not returned to sender; no answer Brammer, [15] 1990 No answer Ninane et al, [18] 1994 No answer Philpott-Howard Answer to first letter: "I will have to contact Pfizer as et al, [19] 1993 they have the original data on file, and the paper I wrote was based on data abstracted from this. I will contact the company shortly and let you know as soon as I have the answers." Indicated that he would contact Pfizer also after the telephone calls; no answer Troke (Pfizer Central Answer to letter: "I am unable to devote the time Research, Sandwich, required to do this work ... I have passed your England) request on to colleagues in New York who may be of assistance." Author and/or Sources of Employee Support [+] Anaissie et al, [13] 1996 Pfizer grant support Bodey et al, [14] 1994 Pfizer grant-in-aid Lake et al, [16] 1996 None declared Marie et al, [29] 1993 Pfizer performed the randomization Lapierre et al, [28] 1992 Pfizer performed the randomization Silling-Engelhardt None declared et al, [20] 1994 (abstract only) Viscoli et al, [21] 1996, Pfizer educational Viscoli et al, [26] 1995 grant Consiglio Nazionale delle Richerche Akiyama et al, [12] 1993 Pfizer thanked for statistical analysis Menichetti et al, [17] 1994 Pfizer grant support, Consiglio Nazionale delle Richerche Meunier et al, [8] 1991 Pfizer support Teshima et al, [24] 1994 None declared Finke, [25] 1990 Pfizer support Brammer, [15] 1990 Pfizer employee, sole author Ninane et al, [18] 1994 Pfizer grant support Philpott-Howard Pfizer employee as et al, [19] 1993 coauthor Troke (Pfizer Central Pfizer employee Research, Sandwich, England) (*.)Quotations refer to responses in writing. (+.)Information regarding sources of support is provided in the original articles. Comparison of Nystatin vs Placebo in Preventing Colonization No. of Colonizations/ Total Patients Source, y Experimental Control Weight, % Buchanan at al, [1] 1985 24/39 27/39 29.0 Epstein et al, [2] 1992 13/50 11/36 27.6 Savino at al, [3] 1994 16/75 19/72 43.5 Total 53/164 57/147 100.1 OR (95% CI, Fixed-Effects Source, y Model) Buchanan at al, [1] 1985 0.71 (0.28-1.81) Epstein et al, [2] 1992 0.80 (0.31-2.07) Savino at al, [3] 1994 0.76 (0.36-1.62) Total 0.76 (0.46-1.25) Comparison of Fluconazole vs Nystatin in Preventing Fungal Invasion and Mortality No. of Fungal Invasions/ Total Patients Source, y Experimental Control Weight, % Egger et al, [4] 1995 1/43 2/46 18.4 Ellis et al, [5] 1994 2/42 7/48 51.2 Lumbreras et al, [7] 1996 1/76 4/67 30.4 Total 4/161 13/161 100.0 OR (95% CI, Fixed-Effects Source, y Model) Egger et al, [4] 1995 0.54 (0.05-5.35) Ellis et al, [5] 1994 0.34 (0.09-1.34) Lumbreras et al, [7] 1996 0.25 (0.04-1.51) Total 0.34 (0.13-0.91) No. of Deaths/ Total Patients OR (95% CI, Fixed-Effects Source, y Experimental Control Weight, % Model) Egger et al, [4] 1995 1/43 0/46 2.7 7.92 (0.16-400.21) Ellis et al, [5] 1994 8/42 17/48 48.2 0.45 (0.18-1.12) Flynn et al, [6] 1995 2/94 0/88 5.3 7.01 (0.43-113.07) Lumbreras et al, [7] 1996 10/76 9/67 43.8 0.98 (0.37-2.56) Total 21/255 26/249 100.0 0.79 (0.41-1.49) Comparison of Fluconazole vs Nystatin in Preventing Colonization No. of Colonizations/ Total Patients Source, y Experimental Control Weight, % Egger et al, [4] 1995 11/43 17/46 17.1 Ellis et al, [5] 1994 11/42 23/48 17.2 Flynn at al, [6] 1995 17/72 48/54 16.4 Lumbreras et al, [7] 1996 19/76 35/67 18.3 Pons et al, [12] 1997 27/68 62/66 15.7 Tian et al, [8] 1997 5/40 11/40 15.4 Total 90/341 196/321 100.1 OR (95% CI, Random- Source, y Effects Model) Egger et al, [4] 1995 0.59 (0.24-1.46) Ellis et al, [5] 1994 0.39 (0.16-0.94) Flynn at al, [6] 1995 0.04 (0.01-0.11) Lumbreras et al, [7] 1996 0.30 (0.15-0.62) Pons et al, [12] 1997 0.04 (0.01-0.13) Tian et al, [8] 1997 0.38 (0.12-1.21) Total 0.19 (0.08-0.47) Meta-analysis of trials comparing nystatin with placebo and comparing fluconazole with nystatin in patients with severe disease predisposing to fungal infection. OR indicates odds ratio; CI, confidence interval. Statistical analysis used the [X.sup.2] test for heterogeneity and the z score for the difference between treatments; a z score higher than 1.96 is equivalent to P[less than].05. For Figure 1, [X.sup.2]2 = 0.03 (z score = 1.10); for Figure 2 top, [X.sup.2]2 = 0.26 (z score = 2.16); for Figure 2 bottom, [X.sup.2]3 = 5.36 (z score = 0.74); and for Figure 3, [X.sup.2]5 = 27.58 (z score = 3.57). Data in the Weight, % column may not add to 100% due to rounding. APPENDIX We identified 12 relevant reports, [1-12] of which 3 were subsequently excluded. A trial in which only 12 patients received nystatin had failed due to serious problems with compliance [9]; another reported only the number of "Candida-free" days (which was 18 for both nystatin and placebo) [10]; the third report was a duplicate publication. [11] Of the 9 included trials, 1 was published as an abstract only. [8] The drugs were given prophylactically in 7 trials and as treatment in 2. [6,12] Acute leukemia was the most common disease in 6 trials; 1 trial concerned patients receiving a liver transplant [7]; 1, critically ill surgical and trauma patients [3]; and 1, patients with acquired immunodeficiency syndrome. [12] Nystatin was compared with placebo in 3 trials [1-3] and with fluconazole in 6 [4-8,12] all drugs were given orally. In total, 537 patients received nystatin, 147 placebo, and 378 fluconazole. The dose of nystatin varied from 1.5 million international units [8] to 72 million international units [4] daily. Concealment of treatment allocation was reported in 3 trials. [3,5,6] Blinding was reported in 4 trials; the control group received saline in 1 study [2] and the assessors were blinded in 3 trials. [5,6,12] None of the 3 placebo-controlled trials reported deaths or invasive fungal infection according to our criteria (1 trial reported 5 cases of sepsis for patients taking nystatin and 2 receiving placebo but the definition of sepsis included positive cultures from at least 3 sites).[3] The effect of nystatin was similar to that of placebo on fungal colonization (APPENDIX FIGURE 1); the total number of colonizations for nystatin was 53 of 164 patients, while it was 57 of 147 for placebo (odds ratio, 0.76 [95% CI, 0.46-1.25]). There was no difference between fluconazole and nystatin for mortality (odds ration, 0.79 [95% CI,0.41-1.49]) whereas fluconazole was considerably more effective in preventing invasive fungal infection (odds ratio, 0.34 [95% CI, 0.13-0.91]) and colonization (odds ratio, 0.19 [95% CI, 0.08-0.47]) (APPENDIX FIGURES 2 and 3). There was a marked heterogeneity for colonization (P[less than].001) that was caused by an unusually large effect of fluconazole in the 2 treatment trials (in which the patients had oropharyngeal thrush). [6,12] If these studies are excluded, the heterogeneity disappears and the odds ratio becomes 0.40 (95% CI, 0.26-0.61). Exclusion of the 3 nystatin trials that were not performed in cancer patients [3,7,12] would not alter the perception of nystatin as a drug working at the placebo level. APPENDIX REFERENCES (1.) Buchanan AG, Riben PD, Rayner EN, Parker SE, Ronald AR, Louie TJ. Nystatin prophylaxis of fungal colonization and infection in granulocytopenic patients: correlation of colonization and clinical outcome. Clin Invest Med. 1985;8:139-147. (2.) Epstein JB, Vickars L, Spinelli J, Reece D. Efficacy of chlorhexidine and nystatin rinses in prevention of oral complications in leukemia and bone marrow transplantation. Oral Surg Oral Med Oral Pathol. 1992;73:682-689. (3.) Savino JA, Agarwal N, Wry P, Policastro A, Cerabona T, Austria L. Routine prophylactic antifungal agents (clotrimazole, ketoconazole, and nystatin) in nontransplant/nonburned critically ill surgical and trauma patients. J Trauma. 1994;36:20-25. (4.) Egger T, Gratwohl A, Tichelli A, et al. Comparison of fluconazole with oral polyenes in the prevention of fungal infections in neutropenic patients: a prospective, randomized, single-center study. Support Care Cancer. 1995;3: 139-146. (5.) Ellis ME, Quadri SM, Spence D, et al. The effect of fluconazole as prophyaxis for neutropenic patients on the isolation of Candida spp. from surveillance cultures. J antimicrob chemother. 1994;33:1223-1228. (6.) Flynn PM, Cunningham CK, Kerkering T, et al, for The Multicenter Fluconazole Study Group. Oropharyngeal candidiasis in immunocompromised children: a randomized, multicenter study of orally administered fluconazole suspension versus nystatin. J Pediatr. 1995;127:322-328. (7.) Lumbreras C, Cuervas Mons V, Jara P, et al. Randomized trial of fluconazole versus nystatin for the prophylaxis of Candida infection following liver transplantation. J Infect Dis. 1996;174:583-588. (8.) Tian D, Jian H, Cul X, et al. Prospective study of fluconazole in the prevention of fungal infections in neutropenic patients with acute leukemia and non-Hodgkins lymphoma. In: Program and abstracts of the 20th International Congress of Chemotherapy; June 29-July 3, 1997; Sydney, Australia. Abstract 3246. (9.) Hoppe JE, Friess D, Niethammer D. Orointestinal yeast colonization of paediatric oncologic patients during antifungal prophylaxis: results of quantitative culture and Candida serology and comparison of three polyenes. Mycoses. 1995;38:41-49. (10.) Williams C, Whitehouse JM, Lister TA, Wrigley PF Oral anticandidal prophylaxis in patients undergoing chemotherapy for acute leukemia. Med Pediatr Oncol. 1977;3:275-280. (11.) Ellis ME, Clink H, Ernst P, et al. Controlled study of fluconazole in the prevention of fungal infections in neutropenic patients with haematological malignancies and bone marrow transplant recipients Eur J Clin Microbiol Infect Dis. 1994;13:3-11. (12.) Pons V, Greenspan D, Lozada-Nur F, et al. Oropharyngeal candidiasis in patients with AIDS: randomized comparison of fluconazole versus nystatin oral suspensions. Clin Infect Dis. 1997;24:1204-1207. -- End --
|