Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients

N Engl J Med. 2016 Aug 11;375(6):534-44. doi: 10.1056/NEJMoa1601747. Epub 2016 May 27.

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.).

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Adult
  • Aged
  • Benzamides / administration & dosage*
  • Benzamides / adverse effects
  • Double-Blind Method
  • Drug Administration Schedule
  • Factor Xa Inhibitors / administration & dosage*
  • Factor Xa Inhibitors / adverse effects
  • Female
  • Fibrin Fibrinogen Degradation Products / analysis
  • Hemorrhage / chemically induced
  • Hospitalization
  • Humans
  • Male
  • Middle Aged
  • Pulmonary Embolism / prevention & control
  • Pyridines / administration & dosage*
  • Pyridines / adverse effects
  • Risk Factors
  • Ultrasonography
  • Venous Thromboembolism / prevention & control*
  • Venous Thrombosis / diagnostic imaging
  • Venous Thrombosis / prevention & control

Substances

  • Benzamides
  • Factor Xa Inhibitors
  • Fibrin Fibrinogen Degradation Products
  • Pyridines
  • fibrin fragment D
  • betrixaban

Associated data

  • ClinicalTrials.gov/NCT01583218