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Blood Products Advisory Committee June 14, 2002 Laurence Landow MD

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

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slide1

Hetastarch Administration in Patients Undergoing Open Heart Surgery in Association with Cardiopulmonary Bypass (CPB)

Blood Products Advisory Committee

June 14, 2002

Laurence Landow MD

questions for the committee
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
slide4

Venous tubing (from the right atrium)

Arterial line microfilter

Arterial tubing (to the aorta)

Roller Pump

fda background package
FDA Background Package
  • 5 articles
    • 3 retrospective chart reviews
    • 1 case-control epidemiology study
    • 1 meta-analysis
canver and nichols
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

knutson et al
Knutson et al
  • Chart review
  • “…use of hetastarch … may increase bleeding and transfusion requirements.”

Anesth Analg 2000; 90:801-7

cope et al
Cope et al
  • Chart review
  • “Hetastarch infusion … produces a clinically important impairment in post-cardiac surgical hemostasis.”

Ann Thorac Surg 1997; 63:78-83

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

speakers
Speakers
  • Charles C. Canver MD
  • Gary R. Haynes MD, PhD
  • William Sibbald MD
reason 1
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
reason 2
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
reason 3
Reason # 3
  • Standards of medical care change over time
      • Canver et al: Spanned 8 years
reason 4
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”
reason 5
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
reason 6
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
reason 6 cont d
Reason # 6 (cont’d)
  • Confounding is likely
      • Cope et al: Volume expansion different across groups
reason 6 cont d1
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
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

Reason # 7
reason 8
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
reason 9
Reason # 9
  • Reporting bias is possible
      • Positive findings are reported whereas negative findings are not
conclusion
Conclusion
  • Non-randomized clinical trials tend to exaggerate effect size
questions for the committee1
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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