Characterization of Major and Clinically Relevant Non-Major Bleeds in the APEX Trial

Megan K Yee, C Michael Gibson, Tarek Nafee, Mathieu Kerneis, Yazan Daaboul, Serge Korjian, Gerald Chi, Fahad AlKhalfan, Adrian F Hernandez, Russell D Hull, Alexander T Cohen, Samuel Z Goldhaber, Megan K Yee, C Michael Gibson, Tarek Nafee, Mathieu Kerneis, Yazan Daaboul, Serge Korjian, Gerald Chi, Fahad AlKhalfan, Adrian F Hernandez, Russell D Hull, Alexander T Cohen, Samuel Z Goldhaber

Abstract

Background Among medically ill patients treated with thromboprophylaxis, betrixaban was not associated with an increase in major bleeding compared with enoxaparin, but an increase in clinically relevant non-major (CRNM) bleeding was observed. The aim of this analysis is to describe the severity and clinical consequences of major and CRNM bleeding in the APEX trial. Methods The APEX trial randomized 7,513 hospitalized acutely ill medical patients to receive either enoxaparin for 6 to 14 days or betrixaban for 35 to 42 days. Subjects receiving a concomitant strong p-glycoprotein inhibitor or with creatinine clearance <30 mL/min were administered a reduced dose of study drug. Results A total of 25 (0.7%) and 21 (0.6%) major bleeds occurred in the betrixaban and enoxaparin arms, respectively ( p = NS) and a total of 91 (2.5%) and 38 (1.0%) CRNM bleeds occurred in the betrixaban and enoxaparin arm ( p < 0.001), respectively. Most major bleeds were considered moderate or severe and most CRNM bleeds were considered mild and moderate ( p = NS). One fatal major bleed occurred in each treatment arm. Rates of major or CRNM bleeds resulting in new or prolonged hospitalization (major: 44.0 vs. 28.6%; CRNM: 12.1 vs. 21.1%) or study treatment interruption or cessation (major: 72.0 vs. 71.4%; CRNM: 71.3 vs. 68.4%) were similar between treatment arms ( p = NS). Conclusions In the APEX trial, CRNM bleeds were mild or moderate in nature and had less of a clinical impact than major bleeds. The severity and clinical sequela of bleeds in the betrixaban arm were comparable to those in the enoxaparin arm. Clinical Trial Registration URL: http://www.clinicaltrials.gov .; Unique identifier: NCT01583218.

Keywords: acutely ill patients; betrixaban; clinically relevant non-major bleeding; major bleed; venous thromboembolism.

Conflict of interest statement

Conflict of Interest Megan K. Yee, C. Michael Gibson, and Tarek Nafee have received consulting fees and grant support from Portola Pharmaceuticals during the conduct of the study. Gerald Chi, Adrian Hernandez, Russell Hull, and Robert Harrington have received research grant support from Portola Pharmaceuticals. Alexander Cohen has received grant support, personal fees, and nonfinancial support from Portola Pharmaceuticals during the conduct of the study. Samuel Goldhaber provided consulting for Portola Pharmaceuticals. All other authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Location of major bleeds (A) and location of CRNM bleeds (B). Other bleeds include laceration, hemothorax, vaginal (increased or prolonged menstrual or abnormal vaginal bleeding), bleeding associated with noncardiac surgery, gingival, puncture site, retroperitoneal, subconjunctival/conjunctival, petechial rash/hemorrhage, baker's cyst with intra cyst hemorrhage, and prevertebral space posterior hypopharynx hematoma.
Fig. 2
Fig. 2
Severity of major bleeds (A) and severity of CRNM bleeds (B).
Fig. 3
Fig. 3
Clinical outcomes of major bleeds (A) and clinical outcomes of CRNM bleeds (B). Hosp, required or prolonged hospitalization; Med Tx, required medical treatment; SD Int, study drug interruption; SD Disc, study drug cessation.

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