FDA Safety Communication: Boxed Warning on increased mortality and severe renal injury, and additional warning on risk of bleeding, for use of hydroxyethyl starch solutions in some settings
Date: November 25, 2013 (Revised)
Safety Announcement Update-On November 25, 2013, the U.S. Food and Drug Administration (FDA) approved changes to the prescribing information for the class of hydroxyethyl starch products to add a new Boxed Warning about the risk of mortality and renal replacement therapy. The revised labeling also includes updates to the Contraindications, Warnings and Precautions as well as the Adverse Reactions and Clinical Studies section.
Hydroxyethyl starch (HES) solutions are used for the treatment of hypovolemia (low blood volume) when plasma volume expansion is desired. Recent data have associated administration of these products with an increased risk of severe adverse events when used in certain patient populations.
On September 6-7, 2012, FDA convened a Public Workshop1 in collaboration with the National Heart, Lung, and Blood Institute at the National Institutes of Health, the U.S. Army Materiel Command, Department of Defense, and the Office of the Assistant Secretary of Health, Health and Human Services, to discuss the risks and benefits of HES solutions. Panelists presented data from randomized controlled trials (RCTs), meta-analyses and observational studies (described below in the data summary) that showed increased mortality and/or renal replacement therapy (RRT), i.e., severe renal injury, when HES was used in critically ill adult patients, including patients with sepsis.
FDA has completed its review of the data from the above studies, and an additional RCT study. FDA finds that these studies indicate increased mortality and RRT in critically ill adult patients, including patients with sepsis who are treated with HES solutions. FDA has concluded that HES solutions should not be used in these patient populations, and that a Boxed Warning to highlight the risk of mortality and RRT is warranted. In addition, FDA has reviewed a meta-analysis of studies conducted in patients undergoing open heart surgery in association with cardiopulmonary bypass, and has determined that an additional warning about excessive bleeding is needed in the Warnings and Precautions Section of the package insert.
Patients should be aware of the risks associated with the use of HES solutions and discuss these risks with their healthcare provider.
- Be aware that severe kidney damage has been associated with the use of HES solutions.
- Be sure to follow up with your healthcare provider as requested and follow all instructions. Report any unusual symptoms immediately.
- Symptoms of kidney damage can include:
- change in the frequency, amount, or color of urine
- blood in the urine
- difficulty urinating
- swelling of the legs, ankles, feet, face, or hands
- unusual weakness or fatigue
- nausea and vomiting
- shortness of breath
- Do not use HES solutions in critically ill adult patients, including those with sepsis.
- Avoid use in patients with pre-existing renal dysfunction.
- Discontinue use of HES at the first sign of renal injury.
- 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 hospitalized patients.
- Monitor the coagulation status of patients undergoing open heart surgery in association with cardiopulmonary bypass as excess bleeding has been reported with HES solutions in this population.a Discontinue use of HES at the first sign of coagulopathy.
- Do not use HES products in patients with severe liver disease.
- Monitor liver function in patients receiving HES products.
aHespan (6% HES 450/0.7 in 0.9% Sodium Chloride Injection) is not recommended for use as a cardiac bypass pump prime, while the patient is on cardiopulmonary bypass, or in the immediate period after the pump has been discontinued because of the risk of increasing coagulation abnormalities and bleeding in patients whose coagulation status is already impaired.
Mortality and renal injury requiring renal replacement therapy (RRT)
Four HES products are currently FDA approved for the treatment and prophylaxis of hypovolemia: HESPAN (6% HES 450/0.7b in 0.9% Sodium Chloride Injection; B. Braun Medical Inc), Hetastarch (6% in 0.9% Sodium Chloride Injection, generic equivalent to HESPAN; Teva Pharmaceuticals USA), HEXTEND (6% HES 450/0.7 in physiological solution; BioTime Inc), and Voluven (6% HES 130/0.40 in normal saline; Fresenius Kabi USA, LLC).
Data from randomized controlled trials (RCTs), meta-analyses and observational studies show increased mortality and renal injury requiring RRT in critically ill patients, including patients with sepsis, who are treated with HES. The safety of higher molecular weight (molecular weight: 450 kDa) HES products, (HESPAN, Hetastarch (6%) in 0.9% Sodium Chloride Injection and HEXTEND) was assessed in retrospective studies and meta-analyses. In its analysis, FDA extrapolated safety data from the lower molecular weight HES product to higher molecular weight HES products. This extrapolation was justified because of similarities in chemical structure and mechanism of action between the higher and lower molecular weight HES products. In addition, both higher and lower molecular weight formulations are metabolized by α-amylase into similar smaller fragments until the renal threshold of excretion (45-60 kDa) is reached.2 This fact implies that exposure to smaller molecular weight fragments occurs when higher molecular weight HES products are administered, so that renal toxicity may be anticipated.
Renal injury was not evident in a review of 59 RCTs in which HES products were administered in the operating room to adult and pediatric patients who were undergoing surgery and were followed for a short period of time, i.e., < 7days.3 Possible explanations for the lack of observed toxicity in these surgical populations include low exposure levels; administration of HES to a medically-optimized, comparatively healthy surgery population; short follow-up monitoring; and/or other unknown factor(s).
Based on the totality of the evidence, FDA considers increased mortality and RRT in critically ill adult patients, including patients with sepsis.
Randomized controlled trials, meta-analyses, and observational studies
Increased mortality and/or renal injury requiring RRT in critically ill adult patients, including those with sepsis have been reported in three double-blind, multicenter RCTs published in 2012 comparing HES with crystalloid solution in which treated patients were monitored for 90 days.
- The 6S study compared 6% HES 130/0.42 with Ringer's acetate (not licensed in US) for treatment of hypovolemia in a large population (N=804) of patients with severe sepsis. Death or dialysis-dependence at 90 days were co-primary endpoints; incidence of RRT was a secondary endpoint. Total volume of trial fluid administered (median) was 1500 mL on Day 1, 1500 mL on Day 2, and 1000 mL on Day 3. Mortality (201/398 vs. 172/400; p=0.03) increased independently of increased RRT (87/398 vs. 65/400; p=0.04) in the HES treatment arm. This study demonstrated both increased mortality and serious renal injury at labeled doses of HES, confirming its toxicity.4
- The CRYSTMAS study compared 6% HES 130/0.4 with normal saline in a smaller population (N=196) of severe sepsis patients, as compared to the 6S study. Volume of trial fluid needed to achieve hemodynamic stabilization was the primary endpoint; RRT was a secondary endpoint. Total volume of trial fluid administered (median) was 1000 mL on Day 1, and 500 mL/day on Days 2, 3 and 4, respectively. The difference in mortality was in the direction of an increase with Voluven (40/100 vs. 32/96), but did not reach statistical significance (p=0.33). A trend to increased RRT (p=0.06) was reported in the HES treatment arm (21/100 vs. 11/96).5
- The CHEST study (published after the FDA Public Workshop in 2012) compared 6% HES 130/0.40 with normal saline in a heterogeneous population of adult patients treated in the ICU (N=7000) that included patients with sepsis (N=1937) as well as elective surgery patients and patients with APACHE II score ≥ 25. The primary endpoint was death or dialysis dependency at Day 90. Total volume of trial fluid administered (median) was 1000 mL on Day 0, and 500 mL/day on Day 1, Day 2, and Day 3. The difference in mortality (597/3315 for HES vs. 566/3336 for saline) did not reach statistical significance. HES subjects experienced significantly greater need for RRT (235/3315 vs. 196/3336, p=0.04), but the incidence of RRT in the sepsis subgroup was not reported.6
Meta-analyses and observational studies lend additional support to these findings.
- A Cochrane Collaboration meta-analysis of 34 RCTs using different HES products (130/0.4, 200/0.5, 200/0.6, 70/0.5, 200/0.62, and 450/0.7) to treat hypovolemia found that in a subgroup of studies that captured RRT (9 studies, N=1333) or author-defined kidney failure (12 studies, N=1260) as secondary renal outcomes, a significant increase was observed in HES-treated sepsis patients; this was not observed in HES-treated trauma/surgery patients. The HES used in these studies included 6% HES 130/0.4 (Voluven), 6% HES 130/0.42, 6% HES 200/0.6, and 10% HES 200/0.5.7
- Increased mortality and renal injury requiring RRT were reported in four meta-analyses of RCTs in which different HES formulations were used for fluid resuscitation in critically ill adult patients (N=3156 to 10,391), including patients with sepsis. Most of these studies used 6% HES 130/0.4-0.042. 8,9,10,11
- A single-arm, prospective, observational analysis of adults with severe sepsis (N=1046) who received only one type of colloid for hypovolemia over a 6-year study period reported increased RRT in those receiving Voluven (relative risk, 2.01; 95% CI, 1.34 to 3.02; p<0.001) from 2004 to 2006 compared to those receiving crystalloid from 2008 to 2010.12
- A retrospective evaluation of cardiac surgery patients (N=563) found that pentastarch (10% HES 200/0.45) was independently associated with acute kidney injury (AKI, prespecified as a 50% rise in serum creatinine within 4 days): relative risk 1.08 (1.04 to 1.12; p=0.001). Risk of AKI was dose-dependent, with doses ≥14 mL/kg predicting AKI.13
- A retrospective study of trauma patients (N=2225), 22% (N=497) of whom received HES 450/0.7 as part of their fluid resuscitation regimen, reported increased risk of acute kidney injury: relative risk 1.73 (1.30 to 2.28); increased mortality: relative risk 1.84 (1.48 to 2.29); and increased risk of death or acute kidney injury: relative risk 1.90 (1.59 to 2.27) in HES patients.14
FDA considers increased mortality and renal injury requiring RRT in critically ill adult patients, including patients with sepsis, to be a class effect warranting addition of this new safety information in a Boxed Warning.
In a meta-analysis of 18 RCTs in patients undergoing open heart surgery in association with cardiopulmonary bypass,15 use of different HES products, irrespective of molecular weight or degree of molar substitution, was associated with increased bleeding. FDA considers excess bleeding a class effect warranting addition of this new safety information to the Warning and Precautions Section of the PI.>
- Public Workshop – Risks and Benefits of Hydroxyethyl Starch Solutions
- Westphal M, James MFM, Kozek-Langenecker S, et al. Hydroxyethyl starches: different products – different effects. Anesthesiology 2009;111:187-202
- Van der Linden P, James M, Mythen M, et al. Safety of modern starches used during surgery. Anesth Analg 2013;116:35-48
- Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl starch 130/0.4 versus Ringer's acetate in severe sepsis. N Engl J Med 2012;367:124-34. [Erratum, N Engl J Med 2012;367:481]
- Guidet B, Martinet O, Boulain T, et al. Assessment of hemodynamic efficacy and safety of 6% hydroxyethyl starch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: The CRYSTMAS study. Critical Care 2012, 16:R94
- Myburgh JA, Finfer S, Bellomo R, et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 2012;367:1901-11
- Dart AB, Mutter TC, Ruth CA, et al. Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function. Cochrane Database of Systematic Reviews 2010;Jan 20;1:CD007594
- Haase N, Perner A, Hennings LI, et al. Hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin in patients with sepsis: systematic review with meta-analysis and trial sequential analysis. BMJ 2013;1839 doi: 10.1136/bmj.f839
- Gattas DJ, Dan A, Myburgh J, et al. Fluid resuscitation with 6% hydroxyethyl starch (130/0.4 and 130/0.42) in acutely ill patients: systemic review of effects on mortality and treatment with renal replacement therapy. Intensive Care Med 2013; doi 10.1007/s00134-013-2840-0
- Zarychanski R, Abou-Setta AM, Turgeon AF et al. Association of hydoxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation: a systemic review and meta-analysis. JAMA 2013;309:678-688
- Patel A, Waheed U, Brett SJ. Randomised trials of 6% tetrastarch (hydroxyethyl starch 130/0.4 or 0.42) for severe sepsis reporting mortality: systematic review and meta-analysis. Intensive Care Med 2013; DOI 10.1007/s00134-013-2863-6
- Bayer O, Reinhart K, Kohl M, et al. Effects of fluid resuscitation with synthetic colloids alone on shock reversal, fluid balance, and patient outcomes in patients with severe sepsis: a prospective sequential analysis. Crit Care Med 2012;40:2543-2551
- Rioux JP, Lessard M, De Bortoli B, et al. Pentastarch 10% (250 kDa/0.45) is an independent risk factor of acute kidney injury following cardiac surgery. Critical care medicine 2009;37: 1293-1298
- Lissauer ME, Chi A, Kramer ME, et al. Association of 6% Hetastarch resuscitation with adverse outcomes in critically ill trauma patients. Am J Surgery 2011;202:53-8
- Navickis RJ, Haynes GR, Wilkes MM. Effect of hydroxyethyl starch on bleeding after cardiopulmonary bypass: a meta-analysis of randomized trials. J Thorac Cardiovasc Surg 2012:144:223-30