Results of a systematic evaluation of treatment outcomes for heparin-induced thrombocytopenia in patients receiving danaparoid, ancrod, and/or coumarin explain the rapid shift in clinical practice during the 1990s

Introduction: Randomized controlled trials evaluating treatment of acute, transient, but uncommon diseases are difficult to perform. The prothrombotic adverse drug reaction, heparin-induced thrombocytopenia (HIT), is such an example. During the mid-1980s, the defibrinogenating snake venom, ancrod (+/- warfarin, Canada), or coumarin (warfarin, Canada; phenprocoumon, Germany) alone, were often used to treat HIT. During the 1990s, danaparoid +/- coumarin began to replace ancrod (+/- coumarin), or coumarin alone, for treating HIT, despite danaparoid not being approved for treatment of HIT. Methods: We performed a retrospective evaluation of treatment outcomes from 1986 to 1999, comparing danaparoid coumarin (n=62) versus ancrod +/- coumarin or coumarin alone (controls, n=56). Results: The predefined composite endpoint of adjudicated new, progressive, or recurrent thrombosis (including thrombotic death), or limb amputation, at day 7 (maximum, one event per patient) was significantly tower in danaparoid-treated patients, compared with controls: 8/62 = 12.9% (95% Cl, 4.3-21.5) vs. 22/56 = 39.3% (95% Cl, 26.1-52.5); p = 0.0014. We also found a lower frequency of the composite endpoint at end of study (day 35) in danaparoid-treated patients: 12/62 = 19.4% vs. 24/56=42.9% (p=0.0088). Major bleeding (by day 7) occurred in 7/62 (11.3%) and 16/56 (28.6%) of danaparoid-treated and control patients, respectively (p=0.0211). Conclusions: The replacement of ancrod coumarin, or coumarin alone, by danaparoid ( coumarin) in the mid-1990s for the treatment of HIT was justified by improved efficacy and safety. (c) 2005 Elsevier Ltd. All rights reserved.