Hydroxyethyl starch on kidney and haemostatic function in cardiac surgical patients: is a non-inferiority study design appropriate for this setting?

We read with great interest the paper by Duncan et al. on the effect of hydroxyethyl starch (HES) on kidney and haemostatic function in cardiac surgical patients [1]. In their single‐centre, triple‐blind, parallel group, randomised ‘non inferiority’ trial, the authors tested the primary hypothesis that kidney function was not worse in cardiac surgery patients who received HES compared with patients assigned to receive albumin. The authors concluded that reported evidence proves “lack of harm” due to similar results between the groups. The authors report in their introduction that “according to two studies with inconsistent results, HES appeared to increase mortality and kidney injury in critically ill, including septic patients, who received HES” was the background of their study. To present state‐of‐the‐art clinical evidence is especially relevant when patients are asked to provide informed consent and there is evidence of HES‐associated increased mortality proven by a large meta‐analysis [2, 3]. Controversies regarding peri‐operative use of HES have increasingly been reported to both the US Food and Drugs Administration and the European Medicines Agency [2, 3]. These include the exclusion of patients with pre‐operative impaired renal function that, as reported by the authors, were excluded from the present study. Given these premises it seems more appropriate to convey to readers and stakeholders (including patients and their relatives) a clearer conclusion: only in patients at low risk for postoperative renal damage is there evidence of additional harm when HES is used compared with albumin. Hence, as already underlined by Futier et al. “... these findings do not support the use of HES for volume replacement therapy in such patients” [4]. Furthermore, the present study does not address a more relevant question: what is the benefit? [5]. In light of the existing concerns on HES use, this study leaves several unanswered questions: how should patients be informed when they are asked to participate in a clinical trial that may randomise them to receive HES? How can a prestigious research group consider it appropriate to adopt a ’non‐inferiority’ study design to evaluate the safety profile of a controversial drug such as HES, when any proven beneficial effects (if there are any) remain unanswered?