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Prepublished online as a Blood First Edition Paper on June 28, 2002; DOI 10.1182/blood-2002-02-0471.
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Blood, 1 January 2003, Vol. 101, No. 1, pp. 58-63
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
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
Dietmar Seiffert,
Andrew M. Stern,
William Ebling,
Richard J. Rossi,
Yu Chen Barrett,
Richard Wynn,
Gregory F. Hollis,
Bokang He,
Cathy J. Kieras,
Donna L. Pedicord,
Debra A. Cromley,
Tsushung A. Hua,
Robert B. Stein,
Robert N. Daly,
Anthony Sferruzza,
Henry J. Pieniaszek, and
Jeffrey T. Billheimer
From Bristol-Myers Squibb, Wilmington, DE, and Quest
Diagnostics, San Juan Capistrano, CA.
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/µL
(9 × 1010/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.
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