title: Prospective testing for drug-dependent antibodies reduces the incidence of thrombocytopenia observed with the small molecule glycoprotein IIb/IIIa antagonist roxifiban: implications for the etiology of thrombocytopenia.
abstract: Thrombocytopenia is a relatively common side effect observed during glycoprotein (GP) IIb/IIIa antagonist therapy. With the oral antagonist roxifiban, we observed thrombocytopenia, defined as 50% reduction of platelets over predose values or below 90 000/microL (9 x 10(10)/L), with a frequency of 2% (8 of 386). Thrombocytopenia occurred either early (days 2 to 4) or delayed (days 11 to 16). No additional cases were observed with up to 6 months of treatment. Retrospective analysis provided evidence for drug-dependent antibodies (DDABs) to GP IIb/IIIa in 5 of 6 subjects, suggestive of an immune etiology of thrombocytopenia. The hypothesis that excluding patients based on positive DDAB reaction would reduce the frequency of thrombocytopenia was tested. Patients were screened for DDABs during the study qualification period and, overall, 3.9% of the patients were excluded based on pre-existing DDAB concentrations above a statistically defined medical decision limit. An additional 2.6% were excluded based on therapy-related antibody production during the first 2 weeks. With antibody testing, 0.2% of patients (2 of 1044) developed immune-mediated thrombocytopenia. One case developed a rapidly increasing antibody concentration and presented with thrombocytopenia despite discontinuation of roxifiban therapy. The second case was related to a false-negative test result. The frequency of thrombocytopenia was statistically significantly reduced from 2% to 0.2% (P =.0007) comparing nonscreened and screened patients. Testing for DDABs can reduce the frequency of thrombocytopenia in patients treated with roxifiban and, by analogy, other GP IIb/IIIa antagonists. Thus, DDAB testing may be employed to increase the safety of GP IIb/IIIa antagonists.
authors.affiliation: Bristol-Myers Squibb, Wilmington, DE 19880, USA. dietmar.seiffert@bms.com
authors.forename: Dietmar
authors.initials: D
authors.lastname: Seiffert
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Stern
authors.forename: William
authors.initials: W
authors.lastname: Ebling
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rossi
authors.forename: Yu Chen
authors.initials: YC
authors.lastname: Barrett
authors.forename: Richard
authors.initials: R
authors.lastname: Wynn
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Hollis
authors.forename: Bokang
authors.initials: B
authors.lastname: He
authors.forename: Cathy J
authors.initials: CJ
authors.lastname: Kieras
authors.forename: Donna L
authors.initials: DL
authors.lastname: Pedicord
authors.forename: Debra A
authors.initials: DA
authors.lastname: Cromley
authors.forename: Tsushung A
authors.initials: TA
authors.lastname: Hua
authors.forename: Robert B
authors.initials: RB
authors.lastname: Stein
authors.forename: Robert N
authors.initials: RN
authors.lastname: Daly
authors.forename: Anthony
authors.initials: A
authors.lastname: Sferruzza
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Pieniaszek
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Billheimer
mesh_terms: D000578:Amidines / Q000009:adverse effects* / Q000276:immunology / Q000627:therapeutic use; D001323:Autoantibodies / Q000097:blood*; D001792:Blood Platelets / Q000276:immunology; D006801:Humans; D015994:Incidence; D007555:Isoxazoles / Q000009:adverse effects* / Q000276:immunology / Q000627:therapeutic use; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors / Q000276:immunology*; D012189:Retrospective Studies; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D013997:Time Factors; D014652:Vascular Diseases / Q000150:complications / Q000188:drug therapy
chemical_list: D000578:Amidines; D001323:Autoantibodies; D007555:Isoxazoles; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C118235:roxifiban