Journal of the American College of Surgeons
Volume 205, Issue 2 , Pages 256-265, August 2007

A Phase 3, Randomized, Double-Blind Comparative Study of the Efficacy and Safety of Topical Recombinant Human Thrombin and Bovine Thrombin in Surgical Hemostasis

  • William C. Chapman, MD, FACS

      Affiliations

    • Department of Surgery, Washington University, St Louis School of Medicine, St Louis, MO
    • Corresponding Author InformationCorrespondence address: William C Chapman, MD, Washington University, Department of Surgery, Section of Transplantation, 660 South Euclid Ave, Campus Box 8109, Room 6107 Queeny Tower, St Louis, MO 63110.
    • ,
  • Neil Singla, MD

      Affiliations

    • Huntington Memorial Hospital, Pasadena, CA
    • ,
  • Yuri Genyk, MD, FACS

      Affiliations

    • USC Healthcare Consultation Center, University of Southern California, Los Angeles, CA
    • ,
  • James W. McNeil, MD, FACS

      Affiliations

    • Vascular Surgery Associates, Baton Rouge, LA
    • ,
  • Kenneth L. Renkens Jr, MD, FACS

      Affiliations

    • Indiana Spine Group, Indianapolis, IN
    • ,
  • Thomas C. Reynolds, MD, PhD

      Affiliations

    • ZymoGenetics Inc, Seattle, WA
    • ,
  • Aileen Murphy, MPH

      Affiliations

    • ZymoGenetics Inc, Seattle, WA
    • ,
  • Fred A. Weaver, MD, FACS

      Affiliations

    • USC Healthcare Consultation Center, University of Southern California and LA County Hospital, Los Angeles, CA.

Received 27 February 2007; accepted 5 March 2007. published online 25 June 2007.

Background

Plasma-derived bovine thrombin is used as a topical agent to improve surgical hemostasis, but development of antibodies to bovine hemostatic proteins has been associated with increased bleeding and thrombotic complications. Recombinant human thrombin could reduce the risk of these complications.

Study Design

The objective of this randomized, double-blind, comparative trial was to compare the efficacy, safety, and antigenicity of recombinant human thrombin (rhThrombin) and bovine thrombin as adjuncts to hemostasis in liver resection, spine, peripheral arterial bypass, and dialysis access surgery. Blinded study drug was applied topically to bleeding sites with an absorbable gelatin sponge. The primary efficacy end point was time to hemostasis, summarized as the incidence of hemostasis within 10 minutes. Safety analyses were conducted for 1 month after operation, and the development of antibodies to rhThrombin or to the bovine product was evaluated.

Results

Four hundred one patients completed this trial. Hemostasis was achieved at the time-to-hemostasis evaluation site within 10 minutes in 95% of patients in each treatment group. Overall complications, including operative mortality, adverse events, and laboratory abnormalities, were similar between groups. Forty-three (21.5%) patients receiving bovine thrombin developed antibodies to the product; three patients (1.5%; p < 0.0001) in the rhThrombin group developed antibodies to rhThrombin. None of the three patients who developed antirhThrombin antibodies had abnormal coagulation laboratory results or bleeding, thromboembolic, or hypersensitivity events.

Conclusions

Results of this trial suggest that rhThrombin has comparable efficacy, a similar safety profile, and is considerably less immunogenic than bovine thrombin when used for surgical hemostasis.

Abbreviations and Acronyms: bThrombin, bovine thrombin, INR, international normalized ratio, PAB, peripheral arterial bypass, PT, prothrombin time, rhThrombin, recombinant human thrombin, TTH, time to hemostasis

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 Competing Interests Declared: Authors Murphy and Reynolds were employees of ZymoGenetics, the sponsor of the trial; during the entire study. They are no longer employees of ZymoGenetics.Funding for this trial was provided by ZymoGenetics, Inc.Trial Registration: This study is registered with ClinicalTrials.gov with the identifier NCT00245336.

PII: S1072-7515(07)00456-5

doi:10.1016/j.jamcollsurg.2007.03.020

Journal of the American College of Surgeons
Volume 205, Issue 2 , Pages 256-265, August 2007

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