Open L etter to the E xecutive D irector of the E uropean M edicines A gency concerning the licensing of hydroxyethyl starch solutions for fluid resuscitation

Sir, We have sent this letter to the Executive Director of the European Medicines Agency: The undersigned are concerned that the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee’s (PRAC) recent conclusions on the use of hydroxyethyl starch (HES) will result in harm to patients. In June, the PRAC recommended the suspension of marketing authorization for HES, as the available evidence demonstrated that any possible benefits from HES no longer outweigh its risk. On October 11 2013, the PRAC revised its conclusions, announcing that ‘HES must no longer be used to treat patients with sepsis or burns injuries or in critically ill patients because of an increased risk of kidney injury and mortality. HES solutions may, however, continue to be used in patients to treat hypovolaemia caused by acute blood loss, provided that appropriate measures are taken to reduce potential risks and that additional studies are carried out.’ Adverse effects of HES have been demonstrated in welldesigned investigator-initiated clinical trials in kidney donors, patients with sepsis and in critically ill patients. Experimental and clinical studies strongly suggest that toxicity of HES can be attributed to tissue storage and coagulopathy. We ask the PRAC: what assumptions or clinical data would indicate that the same pathological mechanisms do not apply in patients with hypovolaemia from blood loss? Up to one third of applied HES dose may be stored in the body in clinical settings, contributing to kidney or other organ injury, decreased survival in patients with sepsis and causing pruritus. HES coagulopathy increases the risk of bleeding and need for blood and blood products in patients with sepsis, intensive care patients, those undergoing anaesthesia for major surgery and following blunt trauma. The FDA issued a boxed warning for bleeding in cardiac surgical patients. It seems improbable that the PRAC recommendations ‘that HES solutions should not be used for more than 24 hours and that patients’ kidney function should be monitored for at least 90 days’ will guarantee patient safety. The adverse effects of HES appear to be generic to all HES classes and dose dependent: no safe dose for HES has been defined. In CHEST, increased use of renal replacement therapy in intensive care patients occurred after an average dose of 5 ml/ kg/day, one tenth of the maximal daily dose of 50 ml/kg. Monitoring kidney function for 3 months after use of HES seems impractical, difficult to control and of questionable impact on patient safety. The CRISTAL trial that may have contributed to EMA’s new decision was not designed to assess the safety and efficacy of HES. As an open label trial that combined various colloid or crystalloid fluids in the respective study arms, it does not provide sufficiently robust evidence to contradict the accumulated signal of harm emanating from all the other trials. If HES was a new drug, data from the CRISTAL study could not be included in the regulatory process for drug approval. Given the current safety concerns, it is hard to see why IRBs and patients would give approval or informed consent for further clinical trials, unless data from animal studies strongly suggest conditions where HES might be beneficial. The revised PRAC recommendation may mean that many thousands of patients with hypovolaemia and acute blood loss will continue to receive HES which will expose them to known risks of harm and offer no proven benefit.