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Communications to the Editor |

Hydroxyethyl Starch-Induced Postoperative Bleeding in Cardiac Surgery PatientsHydroxyethyl Starch-Induced Postoperative Bleeding in Cardiac Surgery Patients: More Trials Needed? FREE TO VIEW

Mahlon M. Wilkes, PhD; Roberta J. Navickis, PhD
Author and Funding Information

Affiliations: Hygeia Associates, Grass Valley, CA,  Brigham and Women’s Hospital, Boston, MA

Correspondence to: Mahlon M. Wilkes, PhD, Hygeia Associates, 17988 Brewer Rd, Grass Valley, CA 95949; e-mail: mwilkes@hygeiaassociates.com



Chest. 2004;126(1):311-312. doi:10.1378/chest.126.1.311
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Published online

To the Editor:

Avorn et al1(October 2003) report the results of a retrospective study among 238 coronary artery bypass graft patients at Brigham and Women’s Hospital showing hydroxyethyl starch (HES) exposure to be an independent dose-related risk factor for postoperative bleeding. Their study confirms the findings of five previous retrospective studies26 with a total of 1,812 patients, as well as our metaanalysis7of 16 randomized controlled trials with 653 total patients. Based on previous retrospective studies and the metaanalysis, the Blood Products Advisory Committee of the US Food and Drug Administration voted overwhelmingly in 2002 to support a warning statement on the product labeling of HES regarding the evidence for excessive bleeding in cardiac surgery patients receiving HES.8 In 2003, a warning was added to the product labeling, recommending against the use of HES in cardiac surgery (package insert, Hespan; B. Braun Medical; Irvine, CA; revised March 2003; 6% hetastarch in 0.9% sodium chloride injection).

The copious evidence and recent regulatory action notwithstanding, Avorn et al1 advocate not the avoidance of HES in cardiac surgery but rather another randomized trial. Additionally, it continues to be the institutional policy of Brigham and Women’s Hospital that HES be used in preference to albumin for diverse fluid management indications including cardiac surgery.9 Avorn et al1 adumbrate, without substantiation, that the prior 16 randomized trials were of unsatisfactory quality. Yet, the randomization method was found to be inadequate in only 2 of the 16 trials, and exclusion of patients after study entry was reported in only 4 trials.7 Furthermore, the results were remarkably consistent, with higher postoperative bleeding among cardiac surgery patients receiving HES than albumin in 88% of randomized comparisons, including all three blinded trials.7

Avorn et al1 incorrectly state that in our metaanalysis we “may have omitted some studies that would have been appropriate for consideration.” This was not the case. After an exhaustive search using multiple methods, we included all 16 existing randomized trials of HES vs albumin with available postoperative bleeding data. There were no omissions or exclusions whatever. Indeed, the methodology of the metaanalysis was characterized in a companion editorial as “a model for such studies.”10They also erroneously cite a letter to the editor as suggesting our meta-analysis was biased.11That letter pertained to a different meta-analysis of ours,12and we have elsewhere rebutted the letter.13

Substantial uncertainty no longer persists as to the effects of HES on bleeding after cardiac surgery. We question the value of devoting limited clinical research resources to a seventeenth randomized trial. Resources might more fruitfully be allocated to re-evaluating institutional fluid management polices in light of the evidence outlined above and current HES product labeling.

Avorn, J, Patel, M, Levin, R, et al (2003) Hetastarch and bleeding complications after coronary artery surgery.Chest124,1437-1442. [CrossRef] [PubMed]
 
Villarino, ME, Gordon, SM, Valdon, C, et al A cluster of severe postoperative bleeding following open heart surgery.Infect Control Hosp Epidemiol1992;13,282-287. [CrossRef] [PubMed]
 
Cope, JT, Banks, D, Mauney, MC, et al Intraoperative hetastarch infusion impairs hemostasis after cardiac operations.Ann Thorac Surg1997;63,78-82. [CrossRef] [PubMed]
 
Herwaldt, LA, Swartzendruber, SK, Edmond, MB, et al The epidemiology of hemorrhage related to cardiothoracic operations.Infect Control Hosp Epidemiol1998;19,9-16. [CrossRef] [PubMed]
 
Keyser, EJ, Latter, DA, Morin, JE, et al Pentastarch versus albumin in cardiopulmonary bypass prime: impact on blood loss.J Card Surg1999;14,279-286. [CrossRef] [PubMed]
 
Knutson, JE, Deering, JA, Hall, FW, et al Does intraoperative hetastarch administration increase blood loss and transfusion requirements after cardiac surgery?Anesth Analg2000;90,801-807. [CrossRef] [PubMed]
 
Wilkes, MM, Navickis, RJ, Sibbald, WJ Albumin versus hydroxyethyl starch in cardiopulmonary bypass surgery: a meta-analysis of postoperative bleeding.Ann Thorac Surg2001;72,527-533. [CrossRef] [PubMed]
 
Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research. Proceedings of the Blood Products Advisory Committee 73rd Meeting. Available at: http://www.fda.gov/OHRMS/DOCKETS/ac/02/transcripts/3867T2.doc. Accessed June 15, 2004.
 
Fanikos J. Clinical algorithm development for albumin use: case report. Presented at the 2002 American Society of Health-System Pharmacists Midyear Clinical Meeting, Atlanta, GA, December 10, 2002.
 
Holman, WL Invited commentary. Ann Thorac Surg. 2001;;72 ,.:534. [CrossRef]
 
Gibney, EM Albumin meta-analysis [letter].Ann Intern Med2001;135,1008-1009
 
Wilkes, MM, Navickis, RJ Patient survival after human albumin administration: a meta-analysis of randomized, controlled trials.Ann Intern Med2001;135,149-164. [PubMed]
 
Wilkes, MM, Navickis, RJ Albumin meta-analysis [letter]. Ann Intern Med. 2001;;135 ,.:1009. [PubMed]
 

Hydroxyethyl Starch-Induced Postoperative Bleeding in Cardiac Surgery Patients

To the Editor:

Drs. Wilkes and Navickis are incorrect that it is the institutional policy of our hospital to encourage the use of hetastarch over albumin. The clinical algorithm our division prepared on this topic was revised in light of the bleeding risk we reported in our publication.1We do not disagree with the contention that hetastarch probably increases the risk of postoperative bleeding; this was, after all, the main conclusion of our article. Our main point was not to criticize their metaanalysis on this subject, nor their other work supported by the manufacturers of albumin products; the methodologic concerns we cited were primarily raised by others.23 However, we do not agree with their conclusion that it is time to routinely replace hetastarch with plasma protein products. Clinical policy about such an important matter should be based on large, impeccably conducted randomized controlled clinical trials that compare the relevant choices head-to-head for safety and efficacy. That is particularly necessary in this case because of the important countervailing risks that may be associated with albumin use. A systematic review of randomized controlled trials published in the British Medical Journal by the Cochrane Collaborative found increased mortality rates in critically ill patients randomized to receive albumin.4 That review was recently updated to include a total of 31 randomized controlled trials; this more recent analysis reported a relative risk for death of 1.52 (95% confidence interval, 1.17 to 1.99) in patients randomized to receive albumin vs no albumin, or albumin vs crystalloid. The authors of that report concluded that albumin use would produce one extra death for every 20 critically ill patients receiving albumin.5

As the experience with hormone replacement therapy amply demonstrates,6even carefully conducted epidemiologic studies such as our own cannot exclude the possibility that patient selection and other confounders might produce incorrect conclusions about the efficacy or safety of commonly used medications. Given the frequency of use of colloids and the importance of the risks being considered, it is time for a randomized trial comparing hetastarch with albumin to resolve these issues once and for all. Studies of this kind have begun to appear in the literature.7It is a major failing of our current system for the evaluation of drugs and biological agents that no mechanism exists to ensure that such comparative studies are done promptly, thoroughly, and even-handedly as a matter of routine policy.8

References
Avorn, J, Patel, M, Levin, R, et al Hetastarch and bleeding complications after coronary artery surgery.Chest2003;124,1437-1442. [CrossRef] [PubMed]
 
Durand, M, Chavanon, O Does hydroxyethyl starch increase blood loss in cardiac operations. [letter]Ann Thorac Surg2003;75,1682-1683. [PubMed]
 
Gibney, EM Albumin meta-analysis.Ann Intern Med2001;135,149-164. [PubMed]
 
Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill patients: systematic review of randomized controlled trials.BMJ1998;317,235-240. [CrossRef] [PubMed]
 
Alderson, P, Bunn, F, Lefebvre, C, et al Human albumin solution for resuscitation and volume expansion in critically ill patients (Cochrane methodology review). The Cochrane Library, Issue 4. 2003; John Wiley & Sons. Chichester, UK:.
 
Rossouw, JE, Anderson, GL, Prentice, RL, et al Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial.JAMA2002;288,321-333. [CrossRef] [PubMed]
 
Kuitunen, AH, Hynynen, MJ, Vahtera, E, et al Hydroxyethyl starch as a priming solution for cardiopulmonary bypass impairs hemostasis after cardiac surgery.Anesth Analg2004;,291-297
 
Avorn, J. Powerful medicines: the benefits, risks, and costs of prescription drugs. 2004; Alfred A. Knopf. New York, NY:.
 

Figures

Tables

References

Avorn, J, Patel, M, Levin, R, et al (2003) Hetastarch and bleeding complications after coronary artery surgery.Chest124,1437-1442. [CrossRef] [PubMed]
 
Villarino, ME, Gordon, SM, Valdon, C, et al A cluster of severe postoperative bleeding following open heart surgery.Infect Control Hosp Epidemiol1992;13,282-287. [CrossRef] [PubMed]
 
Cope, JT, Banks, D, Mauney, MC, et al Intraoperative hetastarch infusion impairs hemostasis after cardiac operations.Ann Thorac Surg1997;63,78-82. [CrossRef] [PubMed]
 
Herwaldt, LA, Swartzendruber, SK, Edmond, MB, et al The epidemiology of hemorrhage related to cardiothoracic operations.Infect Control Hosp Epidemiol1998;19,9-16. [CrossRef] [PubMed]
 
Keyser, EJ, Latter, DA, Morin, JE, et al Pentastarch versus albumin in cardiopulmonary bypass prime: impact on blood loss.J Card Surg1999;14,279-286. [CrossRef] [PubMed]
 
Knutson, JE, Deering, JA, Hall, FW, et al Does intraoperative hetastarch administration increase blood loss and transfusion requirements after cardiac surgery?Anesth Analg2000;90,801-807. [CrossRef] [PubMed]
 
Wilkes, MM, Navickis, RJ, Sibbald, WJ Albumin versus hydroxyethyl starch in cardiopulmonary bypass surgery: a meta-analysis of postoperative bleeding.Ann Thorac Surg2001;72,527-533. [CrossRef] [PubMed]
 
Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research. Proceedings of the Blood Products Advisory Committee 73rd Meeting. Available at: http://www.fda.gov/OHRMS/DOCKETS/ac/02/transcripts/3867T2.doc. Accessed June 15, 2004.
 
Fanikos J. Clinical algorithm development for albumin use: case report. Presented at the 2002 American Society of Health-System Pharmacists Midyear Clinical Meeting, Atlanta, GA, December 10, 2002.
 
Holman, WL Invited commentary. Ann Thorac Surg. 2001;;72 ,.:534. [CrossRef]
 
Gibney, EM Albumin meta-analysis [letter].Ann Intern Med2001;135,1008-1009
 
Wilkes, MM, Navickis, RJ Patient survival after human albumin administration: a meta-analysis of randomized, controlled trials.Ann Intern Med2001;135,149-164. [PubMed]
 
Wilkes, MM, Navickis, RJ Albumin meta-analysis [letter]. Ann Intern Med. 2001;;135 ,.:1009. [PubMed]
 
Avorn, J, Patel, M, Levin, R, et al Hetastarch and bleeding complications after coronary artery surgery.Chest2003;124,1437-1442. [CrossRef] [PubMed]
 
Durand, M, Chavanon, O Does hydroxyethyl starch increase blood loss in cardiac operations. [letter]Ann Thorac Surg2003;75,1682-1683. [PubMed]
 
Gibney, EM Albumin meta-analysis.Ann Intern Med2001;135,149-164. [PubMed]
 
Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill patients: systematic review of randomized controlled trials.BMJ1998;317,235-240. [CrossRef] [PubMed]
 
Alderson, P, Bunn, F, Lefebvre, C, et al Human albumin solution for resuscitation and volume expansion in critically ill patients (Cochrane methodology review). The Cochrane Library, Issue 4. 2003; John Wiley & Sons. Chichester, UK:.
 
Rossouw, JE, Anderson, GL, Prentice, RL, et al Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial.JAMA2002;288,321-333. [CrossRef] [PubMed]
 
Kuitunen, AH, Hynynen, MJ, Vahtera, E, et al Hydroxyethyl starch as a priming solution for cardiopulmonary bypass impairs hemostasis after cardiac surgery.Anesth Analg2004;,291-297
 
Avorn, J. Powerful medicines: the benefits, risks, and costs of prescription drugs. 2004; Alfred A. Knopf. New York, NY:.
 
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