FDA Warns of Risks of Kidney Failure, Death With Hydroxyethyl Starch Solution

In June 2013, the Food and Drug Administration (FDA) released a safety alert warning consumers that the intravenous solution hydroxyethyl starch (HES), used to replenish fluids in critically ill patients, causes serious kidney damage and increased rates of death.[1] The FDA issued the alert in response to numerous studies and reviews published in recent years that have consistently demonstrated higher rates of severe kidney failure, major bleeding and death, but no increase in benefit, with HES solutions compared with safer and less expensive intravenous solutions. However, a key committee of the European Medicines Agency (EMA) has taken the stronger step of banning HES because it concluded that there are no patients for whom the benefits of HES outweigh the risks.

Intravenous solutions: crystalloids vs. colloids[2]

Intravenous fluids are used to replenish body fluids that have been lost due to bleeding or dehydration, or to raise severely low blood pressure in critically ill patients. The primary short-term purpose of the administered fluid is to restore normal blood pressure inside the arteries and, in turn, normal blood flow to vital organs, such as the heart and brain.

There are two main categories of intravenous solutions: crystalloid and colloid. Crystalloid solutions contain water and necessary minerals or salts, such as sodium chloride. Colloidal solutions, including HES, have largely the same content as crystalloid solutions but with added protein, starch or other large molecule in varying amounts.

The rationale for using colloidal solutions over crystalloid solutions has been based on the theoretical assumption that the addition of large molecules to the solution would better prevent diffusion of the fluid out of the arteries, where it is most needed in the short term to ensure normal blood flow to vital organs. This speculative benefit, which was later disproved, led to the widespread use of colloid solutions in the latter half of the 20th century.

HES solutions proliferate over five decades

Since their introduction in the 1960s,[3] HES solutions have become a common choice to replenish fluids in critically ill patients. There are currently four FDA-approved HES products for the treatment and prevention of decreased body fluid volume, known as hypovolemia: HESPAN (and its generic version, hetastarch), HEXTEND and VOLUVEN.[4]

The manufacturer of one of the HES brands, VOLUVEN, estimates that 21 million patients received that formulation from 2004 to 2009.[5] The widespread use of this and other colloids has resulted in higher treatment costs, as colloid solutions are considerably more expensive than their crystalloid counterparts.[6]

Definitive evidence shows HES more dangerous than other fluid therapies

Two large randomized trials comparing HES to crystalloid solutions, both published in the New England Journal of Medicine (NEJM) in 2012, confirmed the dangers of HES solutions in critically ill patients.

In June 2012, NEJM published a randomized trial comparing HES to a crystalloid solution, Ringer’s acetate, in approximately 800 critically ill adult patients in the intensive care unit (ICU) with sepsis, a life-threatening group of symptoms caused by a severe infection.[7] Patients were deemed in need of fluid resuscitation by their attending physicians and were given one of the two solutions for up to 90 days. To minimize bias, physicians did not know which solution they were administering. Patients who had previously undergone dialysis or a kidney transplant were excluded from the trial.[8]

The primary purpose of the study was to see how many patients in each group died or were dependent on kidney dialysis 90 days after first receiving either solution. After 90 days, 51 percent of patients receiving HES died, compared with 43 percent of those receiving Ringer’s acetate, a statistically significant 19 percent increase in mortality with HES. HES also led to more cases of acute kidney injury during the trial, including a significantly higher rate of severe kidney injury necessitating dialysis,[9] though by the end of the 90 days, only one patient in each group was still dependent on dialysis. HES also led to a higher rate of severe bleeding episodes and significantly more blood transfusions.

Another, much larger trial of HES therapy was published in NEJM in October 2012. The trial randomized 7,000 critically ill adult patients in the ICU with a variety of conditions necessitating fluid resuscitation to receive HES or standard saline (sodium chloride) solution until discharge or death, or after 90 days, whichever came first.[10] Patients with severe kidney disease and those currently undergoing dialysis were excluded from the study.[11]

By the end of the 90-day period, those receiving HES died at a slightly higher rate (18.0 percent) than saline-infused patients (17.0 percent), but this difference was not statistically significant. Fewer HES patients experienced mild acute kidney injury than saline patients[12] but, as with the June study, patients receiving HES suffered kidney failure (more severe kidney injury) at higher rates and had to receive dialysis significantly more frequently (7.0 percent of patients) than those receiving saline (5.8 percent). Thus, HES more commonly caused severe kidney toxicity than saline solutions, with no increase in survival, and the authors concluded that the study provided no evidence that the use of HES over saline in the ICU setting “… provides any clinical benefit to the patient.”

The evidence against HES grew further in 2013, with the publication of two meta-analyses of HES therapy trials. One paper, a review by the Cochrane research collaboration, reviewed all randomized trials comparing HES to other fluid resuscitation therapies to evaluate kidney effects.[13] The review confirmed that all forms of HES studied increased the rate of severe kidney injury and rates of dialysis.[14]

The other review, published in the Journal of the American Medical Association (JAMA) in February 2013, evaluated kidney injury, death and other important outcomes in all randomized trials through October 2012 of HES solution used in acute fluid resuscitation of critically ill patients.[15] After excluding seven trials conducted by a discredited researcher (see text box below),[16] the review found a 9 percent increased risk of death, a 27 percent increased risk of acute kidney failure and a 32 percent increased risk of requiring dialysis in those receiving HES solutions. HES also led to 42 percent more blood transfusions than other solutions in five trials; however, in three of those trials, there was no significant difference in the total amount of blood transfused across all patients.

In the same issue, JAMA issued an editorial concluding that the results of the meta-analysis “… indicate that the harms of hydroxyethyl starch most likely outweigh the benefits and suggest that these products should not be used for acute volume resuscitation of critically ill patients.”[17]

The publication of a third review in 2013 dealt a further blow to the long-standing idea that colloids (both HES and other formulations) were superior to crystalloid solutions in treating certain critically ill patients. A Cochrane systematic review analyzed all trials comparing colloid solutions (including HES) with crystalloid solutions for fluid resuscitation of critically ill patients.[18] Colloids did not improve death rates (the most important outcome in these patients) when compared with crystalloid solutions, with HES solutions associated with a 10 percent increase in mortality. The Cochrane review authors broadened JAMA’s conclusions regarding HES to all colloid therapy: “As colloids are not associated with an improvement in survival and are considerably more expensive than crystalloids, it is hard to see how their continued use in clinical practice can be justified.”

The FDA opts to keep HES on the market

The FDA’s response to these data included requiring the addition of a black box warning of the risks of kidney injury, blood loss and death to the labels of all HES products. The FDA also warned physicians not to use HES solutions in critically ill patients and those with pre-existing kidney disease.[19]

However, the agency allowed the drug to remain on the market for use in all other patients. In an apparent attempt to justify this decision, the FDA cited data from a systematic review that did not show any increase in adverse kidney effects with HES therapy in surgical patients.[20] Yet the agency itself acknowledged that the trials analyzed in the review had relatively short follow-up periods, which seriously limits the validity of this review given that kidney failure resulting from HES therapy may not manifest until long after the drug is stopped (up to 90 days).[21] In addition, the review’s conclusion that HES did not lead to kidney failure requiring dialysis in surgical patients was based on seven trials with a total of only 790 subjects, and a subsequent letter to the journal that published the review noted that the study was too small to find a significant effect.[22]

The FDA also ignored the fact that the largest clinical trial of HES solution, which showed definitively that HES caused higher rates of kidney failure requiring dialysis, found no difference in effects between surgical patients (who comprised 43 percent of the subjects) and nonsurgical patients.[23]

The agency advised physicians to monitor kidney function and to stop HES therapy “at the first sign of renal injury.”[24] However, this ignores the fact that renal injury may not manifest until well after HES therapy has been administered[25] (up to 90 days) and the “first sign” of renal injury may already indicate irreversible damage, especially in such critically ill patients.[26]

Three days after the FDA’s announcement, the EMA’s Pharmacovigilance Risk Assessment Committee recommended that the product be removed from the market in Europe, because “the benefits of infusion solutions containing hydroxyethyl starch (HES) no longer outweigh their risks.”[27] Given the gravity of the risks involved and the plethora of much safer (and less expensive) alternatives, the FDA’s decision to leave the product on the market is, to say the least, troubling.

What You Can Do

Do not allow HES solution to be used on you, a family member or a friend. In many cases, the solution is administered to patients who may be unconscious and unable to make any treatment decisions. Therefore, you should inform your family members or other medical surrogates in advance not to allow HES to be administered if you require fluid resuscitation while in the hospital. Saline and other crystalloid solutions are much safer and less expensive alternatives[28] to colloidal solutions for replenishing fluids in critically ill patients, and they are just as effective. 

References

[1] Food and Drug Administration Safety Communication. Hydroxyethyl starch. June 24, 2013. http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm358271.htm#professionals. Accessed August 8, 2013.

[2] All information in this section represents standard medical knowledge unless otherwise indicated.

[3] Wise J. Boldt: The Great Pretender. BMJ. 2013 Mar 19;346:f1738.

[4] Food and Drug Administration Safety Communication. Hydroxyethyl starch. June 24, 2013. http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm358271.htm#professionals. Accessed August 8, 2013.

[5] FDA CBER. 1-year Pediatric Post-approval Adverse Event Review: Voluven. October 14, 2009. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM192072.pdf. Accessed August 9, 2013.

[6] Perel P, Roberts I, Ker K. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev. 2013 Feb 28;2:CD000567.

[7] Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med. 2012 Jul 12;367(2):124-34.

[8] Ibid.

[9] Ibid., table 3. “Renal replacement therapy” refers to dialysis or kidney transplant, but there were no transplants occurring in this trial (word-search “transplant”). “Renal replacement therapy or renal SOFA score >3” defined acute kidney injury (see Methods).

[10] Myburgh JA, Finfer S, Bellomo R, et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012 Nov 15;367(20):1901-11.

[11] Ibid. See: supplementary appendix.

[12] Ibid.

[13] Mutter TC, Ruth CA, Dart AB. Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function. Cochrane Database Syst Rev. 2013 Jul 23;7:CD007594.

[14] Ibid.

[15] Zarychanski R, Abou-Setta AM, Turgeon AF, et al. Association of hydroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation: a systematic review and meta-analysis. JAMA. 2013 Feb 20;309(7):678-88.

[16] Ibid.

[17] Antonelli M, Sandroni C. Hydroxyethyl starch for intravenous volume replacement: more harm than benefit. JAMA. 2013 Feb 20;309(7):723-4.

[18] Perel P, Roberts I, Ker K. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev. 2013 Feb 28;2:CD000567.

[19] Food and Drug Administration Safety Communication. Hydroxyethyl starch. June 24, 2013. http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm358271.htm#professionals. Accessed August 8, 2013.

[20] Ibid., referring to: Van Der Linden P, James M, Mythen M, Weiskopf RB. Safety of modern starches used during surgery. Anesth Analg. 2013 Jan;116(1):35-48.

[21] FDA Safety Communication: “Possible explanations for this observation include low exposure levels; administration to a medically-optimized, comparatively healthy surgery population; follow-up monitoring for a brief period of time; and/or other unknown factor(s).” “Need for renal replacement therapy has been reported up to 90 days after HES administration. Continue to monitor renal function for at least 90 days in all patients.”

[22] Takala J, Hartog C, Reinhart K. Safety of modern starches used during surgery: misleading conclusions. Anesth Analg. 2013 Aug;117(2):527-8.

[23] Myburgh JA, Finfer S, Bellomo R, et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012 Nov 15;367(20):1901-11.

[24] Food and Drug Administration Safety Communication. Hydroxyethyl starch. June 24, 2013. http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm358271.htm#professionals. Accessed August 8, 2013.

[25] Food and Drug Administration Safety Communication. Hydroxyethyl starch. June 24, 2013. http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm358271.htm#professionals. Accessed August 8, 2013.

[26] Medical knowledge.

[27] European Medicines Agency. Press release. PRAC recommends suspending marketing authorisations for infusion solutions containing hydroxyethyl starch. June 14, 2013. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/06/news_detail_001814.jsp&mid=WC0b01ac058004d5c1. Accessed August 9, 2013.

[28] Perel P, Roberts I, Ker K. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev. 2013 Feb 28;2:CD000567.

[29] Wise J. Boldt: the great pretender. BMJ. 2013 Mar 19;346:f1738.

[30] Ibid.

[31] Ibid.

[32] Editors-in-chief statement regarding published clinical trials conducted without IRB approval by Joachim Boldt. Minerva Anestesiol. 2011 May;77(5):562-3.

[33] Mutter TC, Ruth CA, Dart AB. Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function. Cochrane Database Syst Rev. 2013 Jul 23;7:CD007594. See also Perel P, Roberts I, Ker K. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev. 2013 Feb 28;2:CD000567.