Meet the New Hydroxyethyl Starch, Same as the Old Hydroxyethyl Starch?

To the Editor I read the recent article by Miyao and Kotake1 on the safety of hydroxyethyl starch (HES) 130/0.4 with great interest and more than a little concern. The authors suggest that kidney damage previously observed in studies with HES in critically ill patients may only be attributable to earlier generations of HES. The authors also suggest that HES 130/0.4 is not associated with an increased risk of acute kidney injury (AKI) because no significant difference was found versus control subjects (ie, patients who did not receive HES rather than alternative fluid as active comparator). There are several issues evident with the statistical methodology used in this study that were not mentioned as limitations: The analysis of the primary endpoint (ie, incidence of AKI) was not conducted using a paired statistical test. A paired analysis is the usual approach for propensity score matching and would likely have resulted in a narrower confidence interval around the odds ratio and an even lower P value (ie, <.07). Thus, a statistically significant increase in the rate of AKI with HES would likely be evident (P < .05), reversing the interpretation of the primary outcome. The length of follow-up for the primary outcome of AKI occurrence was only 7 days (ie, the minimum observation time required).2 A longer follow-up might have seen the between-group difference increase due to delayed-onset AKI, and statistical significance may have been reached. By comparison, the recently published Fluid Loading in Abdominal Surgery: Saline Versus Hydroxyethyl Starch (FLASH) trial of HES versus saline in surgical patients at increased risk of postoperative kidney injury3 reported AKI up to 14 days as part of the primary composite outcome, and AKI up to 28 days as an exploratory outcome. Stage 1 AKI, according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria, was significantly higher in the HES versus saline group at 14 and 28 days.3 Miyao and Kotake1 acknowledge that their patient population has a relatively low risk of renal injury; thus, it seems reasonable to suggest that a longer follow-up time should have been chosen to ascertain that AKI was not significantly increased in the HES group. There was a potential selection bias due to propensity score matching. Data were discarded if no matching patient was available in the comparator group; >40,000 control patients were omitted as the 2 groups were markedly different before propensity score matching. Furthermore, although 36 different parameters were “balanced” in the matching process, some important patient characteristics may have been omitted (eg, intraoperative hypotension and blood loss [acknowledged by the authors as the main risks for AKI]). This potentially undermines the primary outcome analysis because the groups could not be matched for the main AKI risk factors. Because of the limitations of performing a retrospective database analysis and attempting to match historical patients, as opposed to performing a prospectively designed randomized controlled trial with active control, the conclusions should be stated with caution. However, the conclusions are overstated and selective. In the Key Points, the authors make a large generalization that HES 130/0.4 is safe in surgical patients. A marginally nonsignificant P value (.07) on the primary outcome analysis is interpreted as unquestioned evidence of a lack of association between HES and increased odds of AKI. The secondary outcome highlighted above all others is the lower rate of renal replacement therapy with HES versus control (no HES), whereas other secondary outcomes (increased hospital stay, need for vasopressors, and fluid requirement) were significantly worse with HES, demonstrating that the safety of HES 130/0.4 in surgery patients is questionable. Miyao and Kotake1 repeatedly claim that third-generation HES has different safety and pharmacokinetic profile to earlier formulations. However, there are numerous publications that report that third-generation HES is no different to the previous formulations from a safety standpoint.4–6 Given the important limitations in the design and analysis of the study by Miyao and Kotake1 and the body of evidence to the contrary, the authors’ claim that “6% HES 130/0.4 can be safely used as a volume expander for surgical patients” is inappropriate, unsubstantiated by data, and potentially dangerous. Christian J. Wiedermann, MDInstitute of Public Health, Medical Decision Making and Health Technology Assessment (HTA)