Concerns over use of hydroxyethyl starch solutionsBMJ 2014; 349 doi: https://doi.org/10.1136/bmj.g5981 (Published 10 November 2014) Cite this as: BMJ 2014;349:g5981
- Christiane S Hartog, lecturer1,
- Charles Natanson, senior investigator2,
- Junfeng Sun, staff statistician2,
- Harvey G Klein, department chief3,
- Konrad Reinhart, department head1
- 1Department of Anaesthesiology and Intensive Care Medicine, Centre for Sepsis Care and Control, Jena University Hospital, D-07747 Jena, Germany
- 2Critical Care Medicine Department, National Institutes of Health, Bethesda, MD 20892, USA
- 3Department of Transfusion Medicine, National Institutes of Health, Bethesda
- Correspondence to K Reinhart
- Accepted 4 September 2014
Concerns about serious side effects of hydroxyethyl starch (HES) began to emerge in the 1970s, soon after it was first licensed. The concerns grew after three multicentre randomised trials found that administration of HES in patients who had sepsis or were critically ill was associated with a higher risk of kidney injury and bleeding,1 2 3 and more deaths in patients who had sepsis,1 3 when compared with crystalloids. The trials prompted the German Federal Institute for Drugs and Medical Devices to ask the European Medicines Agency (EMA) to review the use of HES in 2012. The EMA committee (of which KR was a member) recommended suspending all use of HES. However, after manufacturers requested that the decision was reviewed, the UK advised its immediate suspension triggering a second EMA review that decided to permit ongoing HES use under limited circumstances. More than two hundred million units of HES have been administered worldwide during the past 10 years (box). 4 We explain here why we believe that the decision to allow its continued use was not in the best interest of patients.
Use of HES
HES is a synthetic carbohydrate polymer marketed as a volume expander in different molecular weights and degrees of substitution
More than 20 different HES solutions from several manufacturers are available in the European Union and more than 30 preparations worldwide
HES has been used in a variety of clinical settings, including during surgery and to treat hypovolaemia after trauma, burns, and in sepsis, despite a lack of evidence of clinical benefit compared with other intravenous fluids such as albumin and crystalloids5
There is no question that HES can effectively expand blood volume. However, the data submitted to the US Food and Drug Authority for its licence in 1972 would today be considered inadequate to detect harms. The freedom of information requests show that the pivotal clinical trials were uncontrolled, short term studies totalling 315 patients and volunteers observed for less than 24 hours. Subsequent submissions of modified or “improved” products relied on similarly inadequate data, since submissions needed only to demonstrate non-inferiority to earlier HES preparations.6 7 Notably, a meta-analysis of clinical studies of HES up to 2011 found that many would not have been able to detect harmful effects because the studies had inadequate observation periods (median 12 hours), lacked patient relevant endpoints, and used control solutions with a risk profile similar to HES.6 Also, a substantial number of published clinical data promoting HES were produced by one of the manufacturers’ corporate funded speakers, and 88 of that author’s publications were subsequently retracted for scientific fraud in 2011.8
We examined publications evaluating HES and found over 100 almost uniformly favourable reviews during the past decade, of which more than 50 were authored or coauthored by 12 corporate funded investigators.9 The sheer number of industry sponsored publications overwhelmed the publication of carefully performed meta-analyses, 10/12 of which recommended against use of HES.9 There is also evidence of suppression of unfavourable data about HES, including non-publication of negative outcomes (selective outcomes reporting)10 11 12 13 or of entire trials with unfavourable outcomes (selective publication),14 and numerous examples of “positioning” inconclusive HES results in a positive way.9
Harms of HES
In the 1970s it was reported that HES interfered with coagulation15 and was stored in tissue,16 but not until the 1990s were there reports of renal abnormalities associated with HES administration . This may be because renal impairment can be delayed by months and may not be apparent to the surgeon or anaesthetists who performed the procedure. The FDA and BfArM say that their databases have recorded only 39 episodes of kidney failure, and reports of adverse reactions fell in the 1990s despite the concomitant increase in HES sales.
Research has found that HES has been linked with fatal intracranial haemorrhage,17 increased bleeding in patients having cardiac surgery,18 and renal failure (box).19 20 21 Between 2008 and 2012, three large randomised trials by different teams all found higher risks with HES than with other volume expanders (table 1⇓).1 2 3 The first trial showed significantly increased rates of acute renal failure (absolute increase 12.1%) and need for renal replacement therapy (absolute increase 12.2%), increased use of blood products (7.3%), and a higher 90 day mortality (7.1%) in patients with sepsis resuscitated with HES compared with those treated with crystalloid .1 The other two found that modern tetrastarch, which was thought less toxic than earlier HES formulations, was nephrotoxic (absolute increase in number requiring renal replacement therapy 1.2% in critically ill and 5.6% in septic patients)2 3 and increased the need for blood transfusion2 3; one study also found an absolute increase in 90 day mortality of 7.5% in patients with severe sepsis (see data supplement on bmj.com for details).3
Emerging safety concerns
2001: French authorities add a warning label after reports of intracranial bleeding in patients with subarachnoid haemorrhage17
2001: Study finds that patients with severe sepsis resuscitated with starches developed acute kidney failure more frequently than patients receiving gelatin21
2004: FDA issues a warning label because of increased bleeding in cardiac surgery18
2008-12: Three multicentre randomised controlled studies find increased rates of renal failure 1]2 3 and bleeding 1 2 3 associated with HES in critically ill and septic patients and increased risk of death1 3 in septic patients
A subsequent meta-analysis published in JAMA reinforced these findings and increased their generalisability.22 The authors combined data from 28 clinical trials including 10 290 critically ill patients in emergency or intensive care settings (none of the trials evaluating deaths or renal failure was by the fraudulent author). HES was associated with increased mortality (1.51%; 95% confidence interval 0.02% to 3%) compared with other fluids (crystalloids, albumin, and gelatin), and increased the risk of needing renal replacement therapy by 3.12% (0.47% to 5.78%).22 These harms were not isolated to one manufacturer, molecular weight, or molar substitution of HES and probably represent a class effect of starches. The mechanisms of HES toxicity are not known, but adverse consequences may result from the rapid accumulation of HES in tissues and macrophages.16
Sales figures from market analyses estimate that from 2002 to 2012, about 240 million units of HES were sold worldwide.4 In the most recent studies using modern HES preparations (lower molecular weight and molar substitution), an average of 2.2 litres or 4.4 units were administered per patient.7 Up to 55 million patients may therefore have been exposed to HES over the past decade and, based on the risks in the JAMA meta-analysis, thousands may have died or required renal replacement therapy as a result.
Regulatory response to concerns
In 2013, after the three large trials showed harms, the FDA issued a “black box” warning about increased mortality and severe renal injury in critically ill patients, advising that it should not be used in this population.18 At about the same time, an EMA pharmacovigilance risk assessment committee (PRAC) reviewed the evidence and recommended suspension of all marketing authorisations for HES.23 Some manufacturers requested that the EMA re-examine this decision, which meant that suspension throughout Europe was delayed.24 However, the UK Medicines and Healthcare Products Regulatory Agency took independent action and withdrew HES,25 and Italy and Poland also acted to limit its use.
In accordance with EU legislation, the action in the UK triggered further urgent review. A second assessment committee, with different leaders and external advisers, looked at the available data. Although the second committee agreed that HES solutions must not be used in critically ill patients or those with sepsis and burn injuries, it allowed their continued use in patients with hypovolaemia due to acute blood loss within the first 24 hours after elective surgery or trauma, and limited the maximum dose. There was, however, considerable dissent about this decision, with only 19 of the 33 eligible members voting in favour.26 27 The committee also requested large randomised post-marketing clinical trials to establish the efficacy and safety of HES in perioperative and trauma populations.28 This recommendation was ratified by the European Commission in December 2013 and became a legally binding regulation in all member states.29
The 2013 EU regulation created a dilemma for the countries that had banned HES but were now required by EU law to reinstate its use. Although alternative treatments with equivalent efficacy and superior safety profiles are available,5 countries can now be pressured by manufacturers to return HES to pharmacy shelves across Europe. Three of us (KR, CN, CSH) were signatories to an open letter protesting the revised decision, which was sent to the EMA at the end of 2013 by more than 80 clinicians and leaders of medical societies worldwide.30
The case for keeping HES
According to the EMA, important new information from three sources led to the revised decision.28 These were a small unpublished single centre study of HES in sepsis,31 unpublished data from a German intensive care registry sponsored by HES manufacturers and conducted by a marketing and communications agency,32 and data from a new trial of colloids versus crystalloids in critically ill hypovolaemic patients.33 The primary endpoint in this trial, 28 day mortality, was not significantly different in the two arms of this trial. It did find that 90 day mortality was significantly lower in the colloid group, although only before correction for multiple comparisons. Furthermore, the 90 day endpoint was added midway through the trial and patients in the colloid arm received three different colloids, not just HES.33 34 Since all the above new data apply to patients with sepsis or in intensive care, it is puzzling that the committee used them to support its decision to retain HES use in surgical and trauma patients.
According to the detailed assessment report, the second PRAC review of numerous published and unpublished studies provided “some reassurance that the risks of mortality and renal injury in surgical and trauma patients may be lower than those in critically ill and [septic] patients.”27 We analysed the strength of data from these studies based on generally accepted criteria of rigour for clinical trials (table 2⇓). Our analysis suggests that only the three multicentre randomised trials in patients with sepsis or in intensive care1 2 3 had the needed sample size, adequate control fluids, and length of follow-up to evaluate HES safety. The fact that no harmful effects have been identified in surgical populations may therefore be the result of poor study quality rather than an absence of side effects in these patients.
The way forward
The EMA has requested further research but is this feasible? Member states may find it difficult to comply with the EMA’s request for post-marketing studies in perioperative and trauma patients. If trials are designed, ethical review boards, clinical investigators, and patients may question whether participants should consent to receiving a product that has no benefit over alternatives and for which there is evidence for harm in critically ill patients. There is little reason to expect different results in elective surgery or trauma. Notably, a recent meta-analysis of studies investigating use of HES in surgical settings confirmed an increased risk of requiring renal replacement therapy (relative risk=1.44, 95% confidence interval 1.04 to 2.01).35 Replacing acute blood loss in surgical and trauma patients with a product that induces coagulopathy may also be difficult to justify when safer alternatives are available.18 36 37 Postmarketing studies must be rigorously designed with patient relevant outcomes, suitable control fluids, and follow-up of at least 90 days.
While awaiting further studies, we believe that the market authorisation for HES should be suspended for all clinical conditions. We advise doctors to avoid using HES for resuscitation when other fluids are available. Withdrawing marketing authorisation now would not prevent future studies under current regulatory oversight. We believe that manufacturers should use preclinical studies to investigate new formulations of HES designed to eliminate the recognised harms before embarking on further clinical trials.
The data used to approve HES in the 1970s would be insufficient by modern regulatory standards
Three randomised controlled trials found that critically ill recipients are at greater risk of kidney injury requiring dialysis and, in two studies, of death
The FDA has issued a black box warning for HES products in all critically ill adult patients, and it has been withdrawn in the UK and some other European countries
EMA revised its initial decision to withdraw HES and allowed limited use for acute blood loss in trauma and after elective surgery
Studies in such patients are of poor quality and may not have been able to detect harms
Cite this as: BMJ 2014;349:g5981
Contributors and sources: KR, CN, and CSH were authors of one of the randomised controlled trials that triggered the review procedure for HES. KR and CS were coauthors on European consensus guidelines on the use of HES. KR was invited expert on HES for FDA and EMA hearings. HGK is a member of the WHO Expert Committee on Biological Standardization, the Trauma and Resuscitation Committee of the US Department of Defence, and the Expert Committee on Resuscitation Fluids of the US Institute of Medicine. Sources for this article included publicly available documents from the EMA and FDA websites, information about approval and pharmacovigilance data requested from the German regulatory agency and requested from the FDA under the Freedom of Information Act. CSH conceived the paper and wrote the first draft; CN, JS, HGK, and KR contributed to the revisions and final manuscript. All authors approved the final manuscript. KR is the guarantor.
Competing interests: We have read and understood BMJ policy on declaration of interests and declare that KR is unpaid chairman of the Global Sepsis Alliance, which is sponsored by B Braun and CSL Behring. The opinions expressed in this article do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government.
Provenance and peer review: Not commissioned; externally peer reviewed.