1. 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. 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. 4 Roller Pump Venous tubing (from the right atrium) Arterial tubing (to the aorta) Arterial line microfilter

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

6. 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; 118:1616-1620

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

8. 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. 9 Herwaldt et al Case-control study “Patient age and hetastarch were risk factors for hemorrhage”

10. 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. 11 Speakers Charles C. Canver MD Gary R. Haynes MD, PhD William Sibbald MD

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

14. 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. 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. 16 Reason # 3 Standards of medical care change over time Canver et al: Spanned 8 years

17. 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. 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. 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. 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. 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. 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. 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. 24 Reason # 9 Reporting bias is possible Positive findings are reported whereas negative findings are not

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

26. 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