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In evaluating the nephrotoxicity of amphotericin B lipid complex (ABE, AbelcetTM) vs. liposomal amphotericin B (AMB, AmbisomeTM), Tonin et al. [1] examined 2 randomised studies published between 2000 and 2001 and found a higher toxicity with ABE (OR = 3.00, 95% confidence interval (CI) = 1.65–5.45) compared with AMB. On the other hand, Subirà et al. [2] found a lower nephrotoxicity with ABE than with conventional amphotericin B (FUN, FungizoneTM) (OR = 0.188, 95% CI: 0.058–0.602) [2]. Finally, the meta-analysis of Botero Aguirre et al. [3] showed less nephrotoxicity with AMB compared with FUN (OR = 0.383, 95% CI: 0.299–0.491, 10 randomised trials, Analysis 1.1). Trial-sequential analysis (TSA) is an original statistical technique [4] that improves the interpretation of a series of randomised trials by demonstrating that the overall evidence is conclusive (and so no further trials are needed). Likewise, when positive evidence cannot be conclusively demonstrated, TSA conclusively demonstrates the proof of no difference (namely: “futility” when controls receive no active treatment or “equivalence” when controls receive an active treatment), which is a more informative result than no proof of difference. Each meta-analysis can in fact be classified by TSA into four categories (superiority, inferiority, futility/proof of no difference, or inconclusive result). Notably, TSA adopts more conservative thresholds than standard meta-analysis in demonstrating superiority or inferiority or futility/proof of no difference. We applied TSA to re-examine the 14 randomised studies evaluated in the two meta-analyses [1, 3]. Our TSA considered the endpoint of nephrotoxicity as previously defined [1, 3]. The main assumptions of our analysis included two-sided testing, risk of type 1 error at 5%, and power at 80%. Two comparisons were examined (AMB vs. FUN and ABE vs. AMB). In comparing AMB vs. FUN, the intervention effect according to the pre-specified endpoint was set at an event frequency of 26.1% for controls (equal to the meta-analytical event frequency of the 10 control groups) and relative risk reduction of 19.2% (according to the program’s estimate). In the comparison between ABE vs. AMB, the intervention effect was set at an event frequency of 18.8% with relative risk reduction of 50%. As usual, the main result of TSA was expressed through a cumulative z-curve graph [4]. In this graph, the boundaries for concluding superiority or inferiority or futility were calculated according to the O’Brien-Fleming a-spending function. All our analyses employed the statistical software developed by the Copenhagen Trial Unit (TSA software, 2011; downloadable at www.ctu.dk/tsa).

Nephrotoxicity of three formulations of amphotericin B: trial sequential analysis