Equivalent efficacy of hydroxyethyl starch 130/0.4 and human serum albumin: if nothing is the same, is everything different? The importance of context in clinical trials and statistics.

1249 December 2013 D URING the past year, there has been substantial discussion about hydroxyethyl starches (HESs), with some claiming that neither efficacy nor safety has been demonstrated. In this issue of ANEStHESIoloGy, Van der linden et al.1 report a clinical efficacy trial with HES 130/0.4 that has several interesting issues. Some, but not all, are discussed relatively briefly, as space limitations preclude full exposition. only tetrastarches (HES 130/0.4 and 130/0.42) are discussed, as older HESs with larger molecules and greater degree of substitution are outmoded owing to their undesirable effects, most notably, on coagulation and hemostasis2,3 and tissue accumulation.4 First, is the importance of the main finding of Van der linden et al.: an efficacy of HES 130/0.4 equivalent to that of 5% human serum albumin when used in pediatric cardiac surgery (more about “equivalence” below: beginning with the paragraph that starts with “In sub-titling...”). This extends the data from other trials in adults, assessing the efficacy (for which HES was intended), and in doing so demonstrating volume expansion similar to that of other colloids.2,5–7 of some importance, as well, was the secondary finding of a lesser positive fluid balance with HES 130/0.4. lesser positive fluid balance has produced improved outcomes8–10; however, this trial was neither designed nor powered to assess that. Safety data are also presented by Van der linden et al. There were no differences between groups for mortality, biomarkers of renal injury or function, coagulation tests, transfusion of any blood component, or calculated blood loss. Despite the 28-day follow-up and no indication of safety concerns, it is not possible to draw confident conclusions regarding safety from the current publication, as with an HES safety sample size of 31 per group, the power to detect differences was small, and the absence of a specific event (e.g., death) is compatible with a 95% upper confidence limit of an incidence of 9.2%.11 Data regarding safety of HES products are of considerable importance, as recently two randomized, “pragmatic” trials in critically ill patients in intensive care units purported to indicate some safety issues with two different tetrastarches (130/0.42 in the Scandinavian Starch for Severe Sepsis [“6S”] trial12 and 130/0.4 in the Crystalloid versus Hydroxyethyl Starch trial [“CHESt”]).13 However, a number of issues cloud the interpretation of the results of those trials. trial therapy was initiated many hours after intensive care unit admission (approximately 4 h in 6S and 10 h in CHESt), after resuscitation, with fluid boluses with no objective criteria for either initiation or termination of test fluid administration. Central venous pressure at initiation of test fluid therapy was approximately 10 mmHg in both trials and greater after HES administration. The 6S trial enrolled Equivalent Efficacy of Hydroxyethyl Starch 130/0.4 and Human Serum Albumin