Author Insights: An Analysis Excluding Trials by Researcher Under Fire for Misconduct Finds Product Used for Critically Ill Patients Is Harmful

Ryan Zarychanski, MD, MSc, of the University of Manitoba, and colleagues reported they found no clinical benefit for use of hydroxyethyl starch for fluid resuscitation and found evidence of greater risks associated with this drug compared with alternatives. Image: Daniel Gwozdz, University of Manitoba

Ryan Zarychanski, MD, MSc, of the University of Manitoba, and colleagues reported they found no clinical benefit for use of hydroxyethyl starch for fluid resuscitation and found evidence of greater risks associated with this drug compared with alternatives. Image: Daniel Gwozdz, University of Manitoba

A new analysis has found that hydroxyethyl starch (HES), a fluid product used to help resuscitate critically ill patients, does not improve patient survival and may cause harm, according to results published in JAMA today. The results suggest that alleged scientific misconduct by a German scientist may have skewed previous meta-analyses of studies of the product, making it look safer and more useful.

Conflicting data sparked debate among clinicians about the usefulness of HES, a product derived from plant starch, in fluid resuscitation of critically ill patients. That debate intensified in March 2011 when 14 journal editors published a letter reporting the results of an investigation by a panel convened by a German medical association of Joachim Boldt, MD. The letter noted that the medical association was unable to verify whether 88 of Boldt’s published studies had received proper institutional review board approval, leading to the retraction of these articles. Subsequently, the Ludwigshafen Hospital, where Boldt had worked, reported the investigation found evidence of data fabrication and scientific misconduct associated with 10 journal articles by Boldt.

The latest analysis of the data on HES takes into account results from 38 clinical trials involving 10 880 patients, including 7 conducted by Boldt prior to 1999 (the German investigation only investigated articles authored or coauthored by Boldt that were published between 1999 and 2011). The researchers found that patients who received HES did not have a lower mortality rate than those who received other products, and when the 7 Boldt trials were excluded from the analysis, they found that HES was associated with an increased risk of death and kidney injury.

Ryan Zarychanski, MD, MSc, of the University of Manitoba in Winnipeg, Canada, the lead author of the analysis, discussed the findings with news@JAMA via e-mail.

news@JAMA: Why did you and your colleagues decide to conduct this analysis?

Dr Zarychanski: Since our original meta-analysis on this topic in 2009, several important trials specifically designed to evaluate clinically relevant outcomes of efficacy and safety have been published. Furthermore, in recent years the medical community has become aware that many studies conducted by one German investigator have been retracted due to serious scientific misconduct.

Science and clinical decision making evolve; what we believe today will most certainly need to be reevaluated over time. We know that 50% of meta-analyses are out of date [after 5 years], and our previous meta-analysis (in 1999) is no exception. Given the existence of new studies, and the knowledge that previously conducted studies have now been retracted and should no longer be considered as legitimate science, it was important to examine the efficacy and safety of hydroxyethyl starch.

news@JAMA: Do you think your findings will change practice?

Dr Zarychanski: Yes. Our study should prompt physicians to reflect on their use of hydroxyethyl starch in all clinical conditions. In the absence of evidence to suggest HES is effective and safe, it should not be routinely prescribed for acute volume resuscitation.

Although our analyses focused only on acute resuscitation, use of these products in all other clinical conditions should be reevaluated. With the knowledge that HES is associated with harm in acute resuscitation—the patient population it was originally designed and marketed for—the onus is on the prescribers to convince the medical community and our patients that it is safe to use in other patient populations.

Our finding should also prompt hospitals to consider the appropriateness of unrestricted HES use on their formularies and will likely motivate regulatory agencies to consider licensing details pertaining to these products. Clinical guidelines and previous meta-analyses will need to be updated, given the results of our study and with the knowledge that much of the work conducted by Dr J. Boldt has been discredited.

news@JAMA: What did your analysis of Boldt’s trials tell you? How did removing his trials affect the overall analysis?

Dr Zarychanski: Trials conducted by Boldt systematically underreported the harms associated with hydroxyethyl starch. Because the pooled results of Boldt’s studies were so different than the results of the remaining trials, we felt it was not responsible or appropriate to include Boldt’s studies in our final analysis. It is important to realize that evidence of harm associated with the use of HES was present even before we excluded Boldt’s studies. Harms were simply greater when his data were not considered.

news@JAMA: When scientific misconduct is identified, how long does it take to correct the scientific record and change practice?

Dr Zarychanski: The consequences of scientific misconduct can be far-reaching. False results can shape our perceptions regarding the benefit or risk of a given intervention and in turn compromise our ability to adequately care for patients or populations. Since the recognition of scientific misconduct by Dr Boldt, all guidelines and meta-analyses [that include his work] are being updated. This process will occur within a few years; however, the entrenched beliefs based on the original data may take many more years to influence or reverse.

news@JAMA: Are there lessons to be learned from your findings on ensuring the integrity of the scientific literature?

Dr Zarychanski: Dishonesty regrettably exists in every domain of life. Thankfully, the honest folk still outnumber the dishonest by a long shot, I think. In medicine, important structures to mitigate academic dishonesty have been implemented but can still be foiled by those who are intent on deceiving. Mandatory trial registration and mandatory trial reporting has the potential to reduce suppression of trial results. Open access to trial data represents another potentially important method to hold investigators accountable.

The story of hydroxyethyl starch is larger than academic misconduct, however, and is not unique. The remote and recent history of medicine is, unfortunately, rife with examples of drugs and products that were introduced into practice without appropriate knowledge of relevant patient-centered outcomes: hemoglobin [cell]-free oxygen carriers certainly carried oxygen, but their use increased patient mortality; aprotinin, once widely used in cardiac surgery, effectively reduced bleeding but was also found to be associated with increased mortality in an adequately powered randomized trial; Swan-Ganz catheters measured what they were supposed to measure but didn’t improve relevant clinical outcomes.

Prior to the widespread introduction of new therapies and technologies into clinical practice, it should simply not be good enough for these products to do what they were designed to do. These innovations should impact clinical outcomes that matter to patients and be safe.

Categories: Critical Care/Intensive Care Medicine, Evidence-Based Medicine, Journalology/Peer Review/Authorship