1 Hetastarch Administration in Patients Undergoing Open Heart Surgery in Association with Cardiopulmonary Bypass (CPB) Blood Products Advisory Committee June 14, 2002 Laurence Landow MD

2 Questions for the Committee 1. Is the evidence for excessive bleeding in cardiac surgery patients who receive 6 % hetastarch strong enough to warrant a warning statement in the hetastarch labeling? 2. If there is insufficient evidence for a labeling change, should a randomized controlled trial(s) be conducted to answer this question? If a trial(s) is warranted, please comment on Inclusion and exclusion criteria What endpoints and differences are clinically meaningful Major predictors of blood loss

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4 Roller Pump Venous tubing (from the right atrium) Arterial tubing (to the aorta) Arterial line microfilter

5 FDA Background Package 5 articles 3 retrospective chart reviews 1 case-control epidemiology study 1 meta-analysis

6 Canver and Nichols Chart review “Use of hetastarch in primary CPB circuitry is devoid of any added hemorrhagic risk after coronary bypass.” Chest 2000; 118:

7 Knutson et al Chart review “…use of hetastarch … may increase bleeding and transfusion requirements.” Anesth Analg 2000; 90:801-7

8 Cope et al Chart review “Hetastarch infusion … produces a clinically important impairment in post- cardiac surgical hemostasis.” Ann Thorac Surg 1997; 63:78-83

9 Herwaldt et al Case-control study “Patient age and hetastarch were risk factors for hemorrhage”

10 Wilkes et al Meta-analysis “Postoperative blood loss is … lower in patients exposed to albumin than 6 % hetastarch.” Ann Thorac Surg 2001; 72:527-34

11 Speakers Charles C. Canver MD Gary R. Haynes MD, PhD William Sibbald MD

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13 9 Reasons to Question Conclusions Based on Non-Randomized Trials

14 Reason # 1 The treatment arms may not be comparable Different inclusion and exclusion criteria across trials Different severity of illness scores (“risk adjustment”) Different scoring systems used to assess risk

15 Reason # 2 Even with sophisticated statistical techniques, one can never be sure that key outcome predictors have been recognized and adjusted for Recognized risk factors Age, gender, severity of illness Unrecognized/unmeasured risk factors Genetic predisposition Socio-economic status

16 Reason # 3 Standards of medical care change over time Canver et al: Spanned 8 years

17 Reason # 4 Treatment endpoints vary between protocols Knutson et al: “No specific transfusion algorithms used during the study period” “No rigorous guidelines for the infusion of hetastarch, albumin, or crystalloid”

18 Reason # 5 Patient selection and treatment can be biased Canver et al: perfusionist selected which solution to use in the pump prime HES might have been avoided in older patients, patients with renal failure

19 Reason # 6 Confounding is likely Knudson et al: HES vs “non-HES” group lower temperatures on bypass longer times on bypass higher frequency of preoperative anticoagulant use

20 Reason # 6 (cont’d) Confounding is likely Cope et al: Volume expansion different across groups % Receiving Colloid Post-CPB % Receiving Colloid in ICU HES Post-CPB only (N=68)100% HESUnknown HES in ICU only (N=59)14% Albumin100% HES No HES (N=62)40% AlbuminUnknown

21 Reason # 6 (cont’d) Confounding is likely Pump prime Cope et al: Albumin + crystalloid Knutson et al: HES not used Canver et al: HES, crystalloid, albumin, albumin + HES

22 Reason # 7 Adequate statistical power does not ensure lack of bias or confounding ~ 200 subjects required to detect an absolute 10% increase in blood loss Knutson et al (N=445): confounded with respect to CPB time and temperature Canver et al (N=887): biased with respect to patient selection and treatment Cope et al (N=189): confounded with respect to fluid management

23 Reason # 8 The quality of the data is often uneven Endpoints Different Defined differently Not pre-specified Missing or inaccurate data not easily identifiable Different variables collected

24 Reason # 9 Reporting bias is possible Positive findings are reported whereas negative findings are not

25 Conclusion Non-randomized clinical trials tend to exaggerate effect size

26 Questions for the Committee 1. Is the evidence for excessive bleeding in cardiac surgery patients who receive 6 % hetastarch strong enough to warrant a warning statement in the hetastarch labeling? 2. If there is insufficient evidence for a labeling change, should a randomized controlled trial(s) be conducted to answer this question? If a trial(s) is warranted, please comment on Inclusion and exclusion criteria What endpoints and differences are clinically meaningful Major predictors of blood loss