1 European Medicines Agency

Hydroxyethyl starch (HES) containing medicinal products. 2 European Medicines Agency

Hydroxyethyl-starch solutions for infusion to be suspended—CMDh endorses PRAC recommendation. 3 Gårdmark M Notification to the PRAC/EMA secretariat of a referral under article 107i of directive 2001/83/EC. In 2013, the European Medicines Agency (EMA) restricted the use of solutions containing hydroxyethyl-starch (HES) in critically ill patients with sepsis, burns, and impaired kidney function while maintaining authorisation for the treatment of hypovolaemia due to acute blood loss when crystalloids alone are not sufficient.On Jan 12, 2018, the EMA's Pharmacovigilance Risk Assessment Committee (PRAC) recommended the suspension of HES from the European market.On Jan 26, the EMA's Coordination Group for Mutual Recognition and Decentralised Procedures—Human (CMDh) approved this recommendation by 15 to 13. This decision was based on findings from two drug utilisation studies highlighting that HES solutions are still given to patients with sepsis,and after auditing of stakeholders and the ad-hoc expert committee.

4 Annane D

Siami S

Jaber S

et al. Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial. 5 Taylor C

Thompson K

Finfer S

et al. Hydroxyethyl starch versus saline for resuscitation of patients in intensive care: long-term outcomes and cost-effectiveness analysis of a cohort from CHEST. 6 Qureshi SH

Rizvi SI

Patel NN

Murphy GJ Meta-analysis of colloids versus crystalloids in critically ill, trauma and surgical patients. 6 Qureshi SH

Rizvi SI

Patel NN

Murphy GJ Meta-analysis of colloids versus crystalloids in critically ill, trauma and surgical patients. 7 Korach JM

Berger P

Giraud C

Le Perff-Desman C

Chillet P Role of replacement fluids in the immediate complications of plasma exchange. French Registry Cooperative Group. 6 Qureshi SH

Rizvi SI

Patel NN

Murphy GJ Meta-analysis of colloids versus crystalloids in critically ill, trauma and surgical patients. We, attendees of the EMA ad-hoc expert meeting held in London on Dec 18, 2017, recommended to the PRAC against suspending HES. This was because, firstly, in 2013, results from an international, industry-independent trial(involving 2857 patients with acute hypovolaemia in intensive care) found no difference in 28-day mortality between crystalloids and colloids (relative risk [RR] 0·96, 95% CI 0·88 to 1·04; p=0·26), significantly lower 90-day mortality in the colloids group (0·92, 0·86 to 0·99; p=0·03), and more vasopressor-free days (mean difference 1·04, 95% CI −0·04 to 2·10; p=0·03) and ventilator-free days (1·10, 0·14 to 2·06; p=0·01) by day 28. The study found no evidence that colloids increased risk of acute kidney injury (AKI) or any other serious adverse event. Analyses of long-term outcomes from the CHEST trialreported no difference in mortality between patients who received HES and patients who received saline at 6 and 24 months, as well as a comparable mean number of quality-adjusted life-years gained. Results from a systematic reviewof 32 trials and 16 647 patients showed that administration of colloids did not increase mortality in critically ill, trauma, and surgical patients (odds ratio [OR] 0·99, 95% CI 0·92 to 1·06). In surgical patients, colloids did not increase the risk of AKI (p=0·43) or renal replacement therapy (p=0·66). In trauma patients, the OR of AKI was 0·46 (95% CI 0·23 to 0·92) in favour of colloids. Thus, there is no evidence to support suspending HES. Secondly, three ongoing trials (EudraCT numbers 2016-002176-27, 2016-002-163-30, and 2014-005575-84) are comparing HES to crystalloids (two upon request by the PRAC and one funded by the French Agency for Medicines and Health Products), and will inform practice in trauma and in patients having abdominal surgery. Thirdly, the PRAC has not considered our warning that suspending HES might result in serious unmet medical needs when crystalloids are not sufficient, which is a very common situation in acutely ill and perioperative patients. The clinical and economic effects of this recommendation have not been provided. There are insufficient data on balanced crystalloids, gelatins, dextrans, or albumins to promote their use as alternate fluid therapy, particularly in surgical, obstetrical, and trauma patients.HES solutions are also widely used in combination with albumin as plasma replacement during plasmapheresis.Their withdrawal from the European market will increase the use of albumin—a product derived from pooled human plasma—and lead to cost issues and shortage of albumin in many countries. Fourthly, the retrospective drug utilisation studies have serious limitations—eg, absence of appropriate answers when filling in the electronic forms, forcing incorrect answers and erroneous classifications of non-adherence. Notably, results from the two drug utilisation studies already mentioned show that adherence to recommended daily treatment dose and duration was satisfactory, and actual doses and durations were substantially lower than in studies showing increased AKI and mortality.Thus, we recommended reappraising existing drug utilisation studies and launching new studies that are better designed.

Finally, the PRAC has not considered the following recommendations to enhance consumers' adherence: appending the statement “crystalloids alone are not considered sufficient” with “in patients treated with crystalloids”, clarifying the degree of hypovolaemia as acute blood loss of at least 500 mL, including an additional warning on primary containers (such as do not use in sepsis or in critically ill patients), distributing with every bag of HES a chart to fill in and a patient-completed medication form, and a registry prospectively collecting safety data. For these reasons, we strongly believe that the EMA recommendation to suspend HES is not scientifically grounded and is potentially hazardous to patients.

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This online publication has been corrected. The corrected version first appeared at thelancet.com on March 8, 2018

DA was the primary investigator of the CRYSTAL trial, which was funded by the French Ministry of Health. TF-B reports speaker fees from MSD, outside the submitted work. TS reports personal fees from Masimo and Edwards, outside the submitted work; is chair of Scientific Subcommittee 14 (Monitoring, Equipment and Ultrasound) of the European Society of Anaesthesiologists; and is chair of the Cardiovascular Dynamics section of the European Society of Intensive Care Medicine. MK reports lecture fees from the Finnish Red Cross Blood Service. CZ declares no competing interests.