Mortality rates in comparative trials of formulations of amphotericin B.

Sir—Wingard et al. [1] reported a randomized controlled trial of the use of amphotericin B lipid complex (ABLC; Abelcet [The Liposome Company]) versus liposomal amphotericin B (L Amph; AmBisome [Fujisawa Healthcare]) for the empirical treatment of patients with febrile neutropenia that is unresponsive to antibacterial therapy. Subjects were randomized to receive ABLC, 5 mg/kg/ day; L Amph, 3 mg/kg/day; or L Amph, 5 mg/kg/day. ABLC had greater toxicity according to 4 measures: fever, chill/rigors, nephrotoxicity, and toxicity-related discontinuation of therapy. The composite end point of successful response was similar for the 3 treatment groups (table 1). Mortality rates were briefly mentioned but were not discussed at length in the article or the accompanying editorial [1, 2]. As a member of the Antibiotic Decision Support Team at my institution, I review numerous trials of antibiotics. I place considerable emphasis on “allcause intention-to-treat” (ACITT) mortality rates (i.e., all-cause mortality rates determined by intention-to-treat analysis). This outcome measure is relatively free from bias, is always available to investigators, and has clear clinical relevance. ACITT mortality rates also provide a simple measure of the severity of illness in the study population. Four previous L Amph trials reported ACITT mortality rates [3–6]. Two of these 4 trials reported trends in mortality rates that favored the use of L Amph over conventional amphotericin [4, 5], but none of the differences were statistically significant. Reports of 2 previous ABLC trials were published in peer-reviewed journals, but neither mentioned ACITT mortality rates [7, 8]. Wingard and colleagues measured mortality rates at the predefined time of 1 week after administration of the last dose of the study drug (table 1). The ACITT mortality rate was 7% overall, which is a bit lower than the rates of 11% and 9% that were observed in similar recent trials [3, 5]. However, mortality rates differed sharply among the study groups, ranging from 14% for the group that received ABLC, 5 mg/kg/day, to 2% for the group that received L Amph, 5 mg/kg/ day (table 1). This difference in mortality rates was both statistically and clinically significant ( ; number of patients P p .009 needed to treat, 9). The authors should be commended for an excellent trial that provides the best current comparative data on the use of ABLC versus L Amph. I am left with several questions with regard to the application of this trial to my practice. Were there any unusual circumstances related to the differences in mortality rates? Do the authors have any explanation for the surprisingly low mortality rate in the group that received L Amph, 5 mg/kg/ day? For each patient, follow-up to assess mortality rates was dependent on the duration of administration of the study drug. Bias might have been introduced if the study drug had been discontinued at different times for severely ill patients in the 3 groups. Can the authors provide data on ACITT mortality rates at a point in time that is independent of the duration of administration of the study drug (e.g., at 30 days after randomization)? In an editorial [2] that accompanied the article by Wingard et al. [1], Bennett aptly summarized the dilemma we face in balancing the higher toxicity of ABLC with the higher cost of L Amph. He proposed that the ability of individual patients to tolerate expected side effects be included in these decisions. Should we also consider individual mortality risk?