Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients

Alexander T Cohen, Robert A. Harrington, Samuel Z. Goldhaber, Russell D Hull, Brian L Wiens, Alex Gold, Adrian F. Hernandez, C. Michael Gibson, APEX Investigators, Giuseppe Lembo

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Patients with acute medical illnesses are at prolonged risk for venous thrombosis. However, the appropriate duration of thromboprophylaxis remains unknown.

METHODS: Patients who were hospitalized for acute medical illnesses were randomly assigned to receive subcutaneous enoxaparin (at a dose of 40 mg once daily) for 10±4 days plus oral betrixaban placebo for 35 to 42 days or subcutaneous enoxaparin placebo for 10±4 days plus oral betrixaban (at a dose of 80 mg once daily) for 35 to 42 days. We performed sequential analyses in three prespecified, progressively inclusive cohorts: patients with an elevated d-dimer level (cohort 1), patients with an elevated d-dimer level or an age of at least 75 years (cohort 2), and all the enrolled patients (overall population cohort). The statistical analysis plan specified that if the between-group difference in any analysis in this sequence was not significant, the other analyses would be considered exploratory. The primary efficacy outcome was a composite of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism. The principal safety outcome was major bleeding.

RESULTS: A total of 7513 patients underwent randomization. In cohort 1, the primary efficacy outcome occurred in 6.9% of patients receiving betrixaban and 8.5% receiving enoxaparin (relative risk in the betrixaban group, 0.81; 95% confidence interval [CI], 0.65 to 1.00; P=0.054). The rates were 5.6% and 7.1%, respectively (relative risk, 0.80; 95% CI, 0.66 to 0.98; P=0.03) in cohort 2 and 5.3% and 7.0% (relative risk, 0.76; 95% CI, 0.63 to 0.92; P=0.006) in the overall population. (The last two analyses were considered to be exploratory owing to the result in cohort 1.) In the overall population, major bleeding occurred in 0.7% of the betrixaban group and 0.6% of the enoxaparin group (relative risk, 1.19; 95% CI, 0.67 to 2.12; P=0.55).

CONCLUSIONS: Among acutely ill medical patients with an elevated d-dimer level, there was no significant difference between extended-duration betrixaban and a standard regimen of enoxaparin in the prespecified primary efficacy outcome. However, prespecified exploratory analyses provided evidence suggesting a benefit for betrixaban in the two larger cohorts. (Funded by Portola Pharmaceuticals; APEX ClinicalTrials.gov number, NCT01583218.).

Original languageEnglish
Pages (from-to)534-44
Number of pages11
JournalNew England Journal of Medicine
Volume375
Issue number6
DOIs
Publication statusPublished - Aug 11 2016

Keywords

  • Acute Disease
  • Adult
  • Aged
  • Benzamides
  • Double-Blind Method
  • Drug Administration Schedule
  • Factor Xa Inhibitors
  • Female
  • Fibrin Fibrinogen Degradation Products
  • Hemorrhage
  • Hospitalization
  • Humans
  • Male
  • Middle Aged
  • Pulmonary Embolism
  • Pyridines
  • Risk Factors
  • Ultrasonography
  • Venous Thromboembolism
  • Venous Thrombosis
  • Journal Article
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

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  • Cite this

    Cohen, A. T., Harrington, R. A., Goldhaber, S. Z., Hull, R. D., Wiens, B. L., Gold, A., Hernandez, A. F., Gibson, C. M., APEX Investigators, & Lembo, G. (2016). Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients. New England Journal of Medicine, 375(6), 534-44. https://doi.org/10.1056/NEJMoa1601747