Echinocandins - first line in invasive candidiasis: how strong is this 'strong' evidence?

In the previous issue of Critical Care, Kett and colleagues [1] published a post hoc analysis of a randomized controlled trial comparing the effi cacy of anidulafungin versus fl uconazole in non-neutropenic critically ill patients with invasive Candida infections (89% had candidemia). But the authors’ claim that their data support the superiority of anidula fungin may be misleading and raises several concerns. First, the primary endpoint of the study was clinical and microbiological success at the end of intravenous therapy. However, surrogate endpoints must be predictive of the clinically relevant endpoint that is mortality [2]. Th at was not the case, and no diff erence in 28-day mortality was noted (20.2% versus 24.3%; P = 0.57). Second, in the present study [1], the duration of intra venous therapy was unclear, but in their original study [3], patients on anidulafungin received, on average, 3 more days of intravenous therapy than the fl uconazol group. Besides, more patients in the anidulafungin arm had their central venous catheter removed. Th ese facts markedly biased the results and could explain the observed diff erences [4]. Th ird, this was a non-inferiority study [3]. Th erefore, from a statis tical point of view, any conclusions regarding superiority must be interpreted with extreme caution [5]. Finally, at the time of the study design [3], the use of amphotericin B, and not fl uconazole, was recommended in unstable patients with invasive Candida infections. Th erefore, the choice of fl uconazole as a comparator limits the study conclusions even further. We believe that, at present, there is no evidence to support the selection of a specifi c antifungal class in invasive Candida infections [4].

In the previous issue of Critical Care, Kett and colleagues [1] published a post hoc analysis of a randomized controlled trial comparing the effi cacy of anidulafungin versus fl uconazole in non-neutropenic critically ill patients with invasive Candida infections (89% had candidemia). But the authors' claim that their data support the superiority of anidula fungin may be misleading and raises several concerns. First, the primary endpoint of the study was clinical and microbiological success at the end of intravenous therapy. However, surrogate endpoints must be predictive of the clinically relevant endpoint that is mortality [2]. Th at was not the case, and no diff erence in 28-day mortality was noted (20.2% versus 24.3%; P = 0.57). Second, in the present study [1], the duration of intra venous therapy was unclear, but in their original study [3], patients on anidulafungin received, on average, 3 more days of intravenous therapy than the fl uconazol group. Besides, more patients in the anidulafungin arm had their central venous catheter removed. Th ese facts markedly biased the results and could explain the observed diff erences [4]. Th ird, this was a non-inferiority study [3]. Th erefore, from a statis tical point of view, any conclusions regarding superiority must be interpreted with extreme caution [5]. Finally, at the time of the study design [3], the use of amphotericin B, and not fl uconazole, was recommended in unstable patients with invasive Candida infections. Th erefore, the choice of fl uconazole as a comparator limits the study conclusions even further. We believe that, at present, there is no evidence to support the selection of a specifi c antifungal class in invasive Candida infections [4].

Daniel H Kett, Annette C Reboli, Andrew F Shorr and Haran T Schlamm
In response to the letter by Gonçalves-Pereira and Póvoa, we would like to point out that, in our post hoc analysis of seriously ill patients with invasive candidiasis, anidulafungin was more eff ective than fl uconazole in terms of global (combined clinical and microbiological) response at the end of treatment. Recognizing the limitations of our analysis, however, we were unable to conclude that anidulafungin was superior to fl uconazole.
Many of the comments of Gonçalves-Pereira and Póvoa were directed at the original study. Th at study was a prospective, randomized, double-blind phase III trial [3] that incorporated a pre-specifi ed, two-step test for noninferiority and then superiority, an accepted statistical method [6]. Th e primary endpoint of that study was investigator-assessed global response, a commonly accepted endpoint in candidemia studies. Th e diff erence in global response between groups remained signifi cant after adjustment for potential imbalances, including duration of treatment and central line status [3].
We disagree with the claim by Gonçalves-Pereira and Póvoa that previous guidelines did not support the use of fl uconazole as a fi rst-line treatment in unstable patients with candidemia. Th e 2000 guidelines of the Infectious Diseases Society of America (IDSA) recommended either fl uconazole or amphotericin as the primary treatment of candidemia regardless of disease severity and noted that fl uconazole was used successfully in unstable patients [7]. Fluconazole was specifi cally chosen as the active comparator in the phase III trial in response to a call for studies comparing echinocandins to fl uconazole [8].
Th e 2009 guidelines of the IDSA recommend an echinocandin as the initial treatment in seriously ill patients [9]. Our data support this recommendation. Recognizing the limitations of our retrospective analysis,