Letter to the Editor
Risks of Hydroxyethyl Starch 130/0.4 in Cardiac Surgery
Journal of Pharmacy Practice 2014, Vol. 27(1) 17-18 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190013504960 jpp.sagepub.com
Gary R. Haynes, MD, PhD1
In a retrospective study of 146 patients conducted in the United States, Romerill and colleagues aimed to assess the impact of a formulary change from 6% hydroxyethyl starch (HES) 670/ 0.75 (Hextend1, Hospira, Inc, Lake Forest, Illinois, USA) to 6% HES 130/0.4 (Voluven1, Hospira) for volume expansion in coronary artery bypass graft or valve surgery or both.1 The change was associated with reductions in the proportions of patients receiving crystalloids and albumin. No differences were detected in renal function or bleeding. However, before the change only 7 (8.8%) of 80 patients received HES 670/ 0.75, while after the change only 34 (51.5%) of 66 patients received HES 130/0.4. As acknowledged by the authors, the study was underpowered to assess safety end points. They also anticipated that further definitive safety data would be forthcoming from the Crystalloid versus Hydroxyethyl Starch Trial (CHEST) comparing HES 130/0.4 (Voluven) versus 0.9% sodium chloride among 7000 intensive care unit patients in Australia and New Zealand, which has now been reported.2 In CHEST, the baseline characteristics of the 2 randomized groups coincided closely. Some patients were included after emergency or elective noncardiac surgeries of unspecified types. The HES 130/0.4 was administered at the low average daily dose of 526 mL in a relatively low-risk population, as judged by control group mortality of only 17% at 90 days. Nonetheless, over 90 days of follow-up HES 130/0.4 significantly increased renal replacement therapy (RRT), blood product transfusion, liver failure, and total treatment-related adverse events. Disturbing data have also been provided by the Scandinavian Starch for Severe Sepsis/Septic Shock (6S) trial of 798 patients evaluating 6% HES 130/0.42 (Tetraspan1, B. Braun Melsungen AG, Melsungen, Germany), a product not currently available in the United States.3 Conducted in 4 Scandinavian countries, that trial included patients who had undergone both emergency and elective surgeries of unspecified types, and the randomized groups were well matched at baseline. Over an observation period of 90 days, HES 130/0.42 significantly increased mortality, RRT, and blood product transfusion. Meta-analyses of randomized trials have demonstrated that excess mortality, renal failure, and bleeding are class effects of HES solutions.4-6 Patients who underwent cardiac surgery may be particularly susceptible to such risks. A 2001 metaanalysis showed greater postoperative bleeding in cardiopulmonary bypass surgery patients receiving HES than albumin.7
In a more recent meta-analysis of 18 randomized trials, HES significantly increased postoperative blood loss, reoperation for bleeding, and blood product transfusion compared with albumin.4 Exposure to HES 130/0.4 was a potent independent risk factor for RRT (adjusted odds ratio, 2.29; 95% confidence interval, 1.47-3.60) in a newly reported prospective study of 6478 consecutive cardiopulmonary bypass surgery patients.8 Compared with albumin, HES was also an independent risk factor for mortality in a retrospective hospital discharge database study of 19 578 cardiac surgery patients.9 The lack of apparent safety differences observed by Romerill and coworkers likely reflects, at least in part, the comparison of 2 HES solutions with each other rather than with albumin or crystalloid. The need for RRT in only 3 total patients may be attributable both to small sample size and to short follow-up. Romerill et al followed patients only until discharge and presented analyses of bleeding and renal outcomes in relation to time for a maximum period of only 4 days. Renal failure appears to result from cumulative storage of HES in the kidney and is often delayed in onset.10 In one randomized trial, the majority of renal failure cases developed more than 4 days after HES exposure.11 Both mortality and RRT were increased by HES 130/0.4 and HES 130/0.42 in a meta-analysis of randomized trials.12 The accumulated body of safety data does not support the conclusion of Romerill and coworkers that HES 130/0.4 might be ‘‘a reasonable alternative to albumin.’’ The added costs of managing HES-related bleeding complications alone far exceed the cost savings from substituting HES for albumin in cardiac surgery.13 In June 2013 the US Food and Drug Administration issued a Safety Communication recommending against the use of HES solutions in critically ill adult patients due to risk of mortality and renal injury requiring RRT and in cardiopulmonary bypass surgery patients due to risk of excess bleeding.14 In October
1
Director of Anesthesia Services, Regional Medical Director, Cabell Huntington Hospital, AmSol, LLC, Huntington, WV, USA Corresponding Author: Gary R. Haynes, Director of Anesthesia Services, Regional Medical Director, Cabell Huntington Hospital, AmSol, LLC, Huntington, WV, USA. Email: [email protected]
18 2013 the European Medicines Agency announced that HES solutions should no longer be used in critically ill patients due to increased risk of mortality and kidney injury.15 Author’s Note Dr Haynes is a consultant to CSL Behring and Covidien Inc.
References 1. Romerill DB, Toyoda AY, Brodeur BE, et al. Albumin utilization in cardiac surgery after transition to hydroxyethyl starch 130/0.4. J Pharm Pract. 2012;25(6):606-610. 2. Myburgh JA, Finfer S, Bellomo R, et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012;367(20):1901-1911. 3. 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(2):124-134. 4. Navickis RJ, Haynes GR, Wilkes MM. Effect of hydroxyethyl starch on bleeding after cardiopulmonary bypass: a metaanalysis of randomized trials. J Thorac Cardiovasc Surg. 2012; 144(1):223-230. 5. Mutter TC, Ruth CA, Dart AB. Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function. Cochrane Database Syst Rev. 2013;7:CD007594. 6. 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;309(7):678-688. 7. Wilkes MM, Navickis RJ, Sibbald WJ. Albumin versus hydroxyethyl starch in cardiopulmonary bypass surgery: a meta-analysis of postoperative bleeding. Ann Thorac Surg. 2001;72(2):527-533.
Journal of Pharmacy Practice 27(1) 8. Schwarzkopf D, Doenst T, et al. Perioperative fluid therapy with tetrastarch and gelatin in cardiac surgery-a prospective sequential analysis. Crit Care Med. 2013;41(11):2532-2542. 9. Sedrakyan A, Gondek K, Paltiel D, et al. Volume expansion with albumin decreases mortality after coronary artery bypass graft surgery. Chest. 2003;123(6):1853-1857. 10. Bellmann R, Feistritzer C, Wiedermann CJ. Effect of molecular weight and substitution on tissue uptake of hydroxyethyl starch: a meta-analysis of clinical studies. Clin Pharmacokinet. 2012; 51(4):225-236. 11. Schortgen F, Lacherade JC, Bruneel F, et al. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet. 2001;357(9260):911-916. 12. 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: systematic review of effects on mortality and treatment with renal replacement therapy. Intensive Care Med. 2013;39(4):558-568. 13. Herwaldt LA, Swartzendruber SK, Edmond MB, et al. The epidemiology of hemorrhage related to cardiothoracic operations. Infect Control Hosp Epidemiol. 1998;19(1):9-16. 14. Food and Drug Administration. 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. 2013. www.fda.gov/ BiologicsBloodVaccines/SafetyAvailability/ucm358271.htm. Accessed November 11, 2013. 15. European Medicines Agency. PRAC confirms that hydroxyethylstarch solutions (HES) should no longer be used in patients with sepsis or burn injuries or in critically ill patients: HES will be available in restricted patient populations. 2013. www.ema. europa.eu/docs/en_GB/document_library/Press_release/2013/10/ WC500151964.pdf. Accessed November 11, 2013.
Risks of Hydroxyethyl Starch 130/0.4 in Cardiac Surgery
Journal of Pharmacy Practice 2014, Vol. 27(1) 17-18 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190013504960 jpp.sagepub.com
Gary R. Haynes, MD, PhD1
In a retrospective study of 146 patients conducted in the United States, Romerill and colleagues aimed to assess the impact of a formulary change from 6% hydroxyethyl starch (HES) 670/ 0.75 (Hextend1, Hospira, Inc, Lake Forest, Illinois, USA) to 6% HES 130/0.4 (Voluven1, Hospira) for volume expansion in coronary artery bypass graft or valve surgery or both.1 The change was associated with reductions in the proportions of patients receiving crystalloids and albumin. No differences were detected in renal function or bleeding. However, before the change only 7 (8.8%) of 80 patients received HES 670/ 0.75, while after the change only 34 (51.5%) of 66 patients received HES 130/0.4. As acknowledged by the authors, the study was underpowered to assess safety end points. They also anticipated that further definitive safety data would be forthcoming from the Crystalloid versus Hydroxyethyl Starch Trial (CHEST) comparing HES 130/0.4 (Voluven) versus 0.9% sodium chloride among 7000 intensive care unit patients in Australia and New Zealand, which has now been reported.2 In CHEST, the baseline characteristics of the 2 randomized groups coincided closely. Some patients were included after emergency or elective noncardiac surgeries of unspecified types. The HES 130/0.4 was administered at the low average daily dose of 526 mL in a relatively low-risk population, as judged by control group mortality of only 17% at 90 days. Nonetheless, over 90 days of follow-up HES 130/0.4 significantly increased renal replacement therapy (RRT), blood product transfusion, liver failure, and total treatment-related adverse events. Disturbing data have also been provided by the Scandinavian Starch for Severe Sepsis/Septic Shock (6S) trial of 798 patients evaluating 6% HES 130/0.42 (Tetraspan1, B. Braun Melsungen AG, Melsungen, Germany), a product not currently available in the United States.3 Conducted in 4 Scandinavian countries, that trial included patients who had undergone both emergency and elective surgeries of unspecified types, and the randomized groups were well matched at baseline. Over an observation period of 90 days, HES 130/0.42 significantly increased mortality, RRT, and blood product transfusion. Meta-analyses of randomized trials have demonstrated that excess mortality, renal failure, and bleeding are class effects of HES solutions.4-6 Patients who underwent cardiac surgery may be particularly susceptible to such risks. A 2001 metaanalysis showed greater postoperative bleeding in cardiopulmonary bypass surgery patients receiving HES than albumin.7
In a more recent meta-analysis of 18 randomized trials, HES significantly increased postoperative blood loss, reoperation for bleeding, and blood product transfusion compared with albumin.4 Exposure to HES 130/0.4 was a potent independent risk factor for RRT (adjusted odds ratio, 2.29; 95% confidence interval, 1.47-3.60) in a newly reported prospective study of 6478 consecutive cardiopulmonary bypass surgery patients.8 Compared with albumin, HES was also an independent risk factor for mortality in a retrospective hospital discharge database study of 19 578 cardiac surgery patients.9 The lack of apparent safety differences observed by Romerill and coworkers likely reflects, at least in part, the comparison of 2 HES solutions with each other rather than with albumin or crystalloid. The need for RRT in only 3 total patients may be attributable both to small sample size and to short follow-up. Romerill et al followed patients only until discharge and presented analyses of bleeding and renal outcomes in relation to time for a maximum period of only 4 days. Renal failure appears to result from cumulative storage of HES in the kidney and is often delayed in onset.10 In one randomized trial, the majority of renal failure cases developed more than 4 days after HES exposure.11 Both mortality and RRT were increased by HES 130/0.4 and HES 130/0.42 in a meta-analysis of randomized trials.12 The accumulated body of safety data does not support the conclusion of Romerill and coworkers that HES 130/0.4 might be ‘‘a reasonable alternative to albumin.’’ The added costs of managing HES-related bleeding complications alone far exceed the cost savings from substituting HES for albumin in cardiac surgery.13 In June 2013 the US Food and Drug Administration issued a Safety Communication recommending against the use of HES solutions in critically ill adult patients due to risk of mortality and renal injury requiring RRT and in cardiopulmonary bypass surgery patients due to risk of excess bleeding.14 In October
1
Director of Anesthesia Services, Regional Medical Director, Cabell Huntington Hospital, AmSol, LLC, Huntington, WV, USA Corresponding Author: Gary R. Haynes, Director of Anesthesia Services, Regional Medical Director, Cabell Huntington Hospital, AmSol, LLC, Huntington, WV, USA. Email: [email protected]
18 2013 the European Medicines Agency announced that HES solutions should no longer be used in critically ill patients due to increased risk of mortality and kidney injury.15 Author’s Note Dr Haynes is a consultant to CSL Behring and Covidien Inc.
References 1. Romerill DB, Toyoda AY, Brodeur BE, et al. Albumin utilization in cardiac surgery after transition to hydroxyethyl starch 130/0.4. J Pharm Pract. 2012;25(6):606-610. 2. Myburgh JA, Finfer S, Bellomo R, et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012;367(20):1901-1911. 3. 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(2):124-134. 4. Navickis RJ, Haynes GR, Wilkes MM. Effect of hydroxyethyl starch on bleeding after cardiopulmonary bypass: a metaanalysis of randomized trials. J Thorac Cardiovasc Surg. 2012; 144(1):223-230. 5. Mutter TC, Ruth CA, Dart AB. Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function. Cochrane Database Syst Rev. 2013;7:CD007594. 6. 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;309(7):678-688. 7. Wilkes MM, Navickis RJ, Sibbald WJ. Albumin versus hydroxyethyl starch in cardiopulmonary bypass surgery: a meta-analysis of postoperative bleeding. Ann Thorac Surg. 2001;72(2):527-533.
Journal of Pharmacy Practice 27(1) 8. Schwarzkopf D, Doenst T, et al. Perioperative fluid therapy with tetrastarch and gelatin in cardiac surgery-a prospective sequential analysis. Crit Care Med. 2013;41(11):2532-2542. 9. Sedrakyan A, Gondek K, Paltiel D, et al. Volume expansion with albumin decreases mortality after coronary artery bypass graft surgery. Chest. 2003;123(6):1853-1857. 10. Bellmann R, Feistritzer C, Wiedermann CJ. Effect of molecular weight and substitution on tissue uptake of hydroxyethyl starch: a meta-analysis of clinical studies. Clin Pharmacokinet. 2012; 51(4):225-236. 11. Schortgen F, Lacherade JC, Bruneel F, et al. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet. 2001;357(9260):911-916. 12. 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: systematic review of effects on mortality and treatment with renal replacement therapy. Intensive Care Med. 2013;39(4):558-568. 13. Herwaldt LA, Swartzendruber SK, Edmond MB, et al. The epidemiology of hemorrhage related to cardiothoracic operations. Infect Control Hosp Epidemiol. 1998;19(1):9-16. 14. Food and Drug Administration. 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. 2013. www.fda.gov/ BiologicsBloodVaccines/SafetyAvailability/ucm358271.htm. Accessed November 11, 2013. 15. European Medicines Agency. PRAC confirms that hydroxyethylstarch solutions (HES) should no longer be used in patients with sepsis or burn injuries or in critically ill patients: HES will be available in restricted patient populations. 2013. www.ema. europa.eu/docs/en_GB/document_library/Press_release/2013/10/ WC500151964.pdf. Accessed November 11, 2013.
