Systematic analysis of hydroxyethyl starch (HES) reviews: proliferation of low-quality reviews overwhelms the results of well-performed meta-analyses

Abstract

Purpose: Hydroxyethyl starch (HES) is a synthetic colloid used widely for resuscitation despite the availability of safer, less costly fluids. Numerous HES reviews have been published that may have influenced clinicians' practice. We have therefore examined the relationship between the methodological quality of published HES reviews, authors' potential conflicts of interest (pCOI) and the recommendations made.

Methods: Systematic analysis of reviews on HES use.

Results: Between 1975 and 2010, 165 reviews were published containing recommendations for or against HES use. From the 1990s onwards, favorable reviews increased from two to eight per year and HES's share of the artificial colloid market tripled from 20 to 60 %. Only 7 % (12/165) of these reviews of HES use contained meta-analyses; these 7 % had higher Overview Quality Assessment Questionnaire (OQAQ) scores [median (range) 6.5 (3-7)] than reviews without meta-analysis [2 (1-4); p < 0.001]. The rates of recommending against HES use are 83 % (10/12) in meta-analyses and 20 % (31/153) in reviews without meta-analysis (p < 0.0001). Fourteen authors published the majority (70/124) of positive reviews, and ten of these 14 had or have since developed a pCOI with various manufacturers of HES.

Conclusions: Low-quality HES reviews reached different conclusions than high-quality meta-analyses from independent entities, such as Cochrane Reviews. The majority of these low-quality positive HES reviews were written by a small group of authors, most of whom had or have since established ties to industry. The proliferation of positive HES reviews has been associated with increased utilization of an expensive therapy despite the lack of evidence for meaningful clinical benefit and increased risks. Clinicians need to be more informed that marketing efforts are potentially influencing scientific literature.

Fig. 1

Study flow. *Excluded languages: Japanese, Russian, Serbocroatian, Polish, Danish, Swedish, Spanish, Portuguese, Chinese, Lithuanian, Czech, Italian. †Unrelated conditions: ovarian hyperstimulation syndrome, retinal vein occlusion, small-volume resuscitation, idiopathic sensorineural hearing loss, eclampsia, diabetic ketoacidosis, chronic obstructive lung disease, polymer science, pharmacokinetics, apheresis, cell harvest, blood component harvest and organ preservation

Fig. 2

Quality assessment of hydroxyethyl starch (HES) reviews by OQAQ score. Reviews with an overall Overview of Quality Assessment Questionnaire (OQAQ) score of ≥5 are regarded as having minor or minimal flaws, i.e., being of high quality. HES meta-analyses achieved significantly higher OQAQ scores [n = 12; median (range) 6.5 (3–7)] than HES reviews without a meta-analysis [n = 153; 2 (1–4); p < 0.0001]. Meta-analyses that were not in favor of HES use achieved significantly higher OQAQ scores [n = 10, 7 (4–7)] than favorable meta-analyses [n = 2, 3 (3–3); n = 0.02]

Fig. 3

Hydroxyethyl starch recommendation in the meta-analyses and reviews without a meta-analysis. If a recommendation was made in a review with a meta-analysis, 83 % of the recommendations were unfavorable. In contrast, only 20 % of reviews without a meta-analysis made an unfavorable recommendation (83 vs. 20 %, respectively; p < 0.0001, Fisher’s exact test). The results are virtually identical if only studies from 2000 to 2010 are included (lower panel), the years in which HES meta-analyses began to be published

Fig. 4

Hydroxyethyl starch reviews and HES consumption. The number of HES reviews increased after 1990, and most of these contained a recommendation (a). Favorable reviews in particular increased dramatically during this period in which the HES market share of worldwide artificial colloid consumption tripled from approx. 20 % [43] to approx. 60 % [44] (b)

Fig. 5

Hypothetical statements made in HES reviews without meta-analysis (n = 153). In reviews without a meta-analysis that recommended HES use, 72 % (88/122) stated that side effects were manageable (a), 55 % (67/122) stated that HES probably had additional beneficial effects beyond plasma expansion (b), and 65 % (79/122) stated that newer preparations of HES were likely to be safer (c). In contrast, in reviews without a meta-analysis that expressed an unfavorable recommendation with respect to HES use, 13 % (4/31) claimed that side effects were manageable (a), 26 % (8/31) claimed HES probably had additional beneficial effects (b), and 26 % (8/31) claimed that newer HES solutions were likely to be safer (c). a 72 versus 13 % (p “ 0.0001), b 55 versus 26 % (n = 0.005), c 65 versus 26 % (n = 0.0002), respectively, by Fisher’s exact test