Topical bovine thrombin and adverse events: a review of the literature.

Objective: To review published evidence suggesting a link between topical bovine thrombin (TBT) and important adverse events (AEs).

Research Design And Methods: English language articles and abstracts were obtained from MEDLINE using combinations of text and MeSH terms for thrombin, bovine thrombin and their trade names. References from summary articles were also retrieved. Published case reports, review articles, and retrospective, prospective or observational studies involving either immunogenicity or AEs were selected for further assessment. Retrieved articles were evaluated separately as AE case reports, quantitative studies of antibodies, or quantitative studies of AEs.

Main Outcome Measures: Presence of case causal information, temporal pattern of case report publication, reproducibility of aggregate data findings, and study design features.

Results: The major limitations of reviewed publications were insufficient information regarding TBT and other exposures, and designs in which linkage between laboratory immune phenomena and AEs could not be evaluated. While immunogenicity studies did support an increased risk for post-TBT antibodies, there was no consistent evidence that this led to an increased AE risk or severity. Common evidentiary deficiencies included case reports from high incidence environments, studies of combination or mixture products, biased study designs, lack of patient-level exposure data, inadequate control groups and insufficient sample sizes. The best designed study (a randomized, controlled comparison of TBT to a recombinant bovine product) documented post-TBT antibody production, but no important efficacy or AE differences. An examination of publication dates for case reports showed a peak between 1992 and 1994 followed by a substantial drop. Since 1997 the number of published AE case reports has continued to decline.

Conclusions: TBT increases the risk for antibody elevations in patients. A careful review of published evidence does not show that either TBT itself or any associated elevations in anti-bovine antibodies are risk factors for clinically important AEs.