Results of the phase 3 APEX study suggest extended treatment with betrixaban may provide a benefit over standard-duration enoxaparin as thromboprophylaxis for patients with acute medical illnesses.
The study’s primary efficacy outcome was a composite of asymptomatic, proximal deep-vein thrombosis (DVT) and symptomatic venous thromboembolism (VTE).
Among patients with an elevated D-dimer level, there was no significant difference between the treatment arms with regard to the primary efficacy outcome.
However, there was a significant difference between the treatment arms in the entire study cohort and among a cohort of patients who either had an elevated D-dimer level or were 75 and older.
“In a pre-specified subgroup of medically ill patients who were D-dimer positive, extended-duration betrixaban demonstrated a reduction in VTE events approaching statistical significance,” explained study author C. Michael Gibson, MD, of Beth Israel Deaconess Medical Center in Boston, Massachusetts.
“In the pre-specified exploratory analyses of central lab D-dimer values and in progressively larger cohorts, including all study patients, the data demonstrated a consistent and significant reduction in VTE with betrixaban, with no statistical difference in major bleeding between the betrixaban and enoxaparin arms.”
These results were presented at the 62nd Annual International Society on Thrombosis and Haemostasis Scientific and Standardization Committee Meeting in Montpellier, France, and published simultaneously in NEJM.
This study was supported by Portola Pharmaceuticals, the company developing betrixaban.
The trial enrolled 7513 patients who were hospitalized for acute medical illnesses. The patients were randomized to receive:
- Subcutaneous enoxaparin (40 mg once daily) for 10 ± 4 days plus oral placebo for 35 to 42 days (n=3754)
- Or subcutaneous placebo for 10 ± 4 days plus oral betrixaban (80 mg once daily) for 35 to 42 days (n=3759).
Results
The researchers performed sequential analyses in 3 prespecified cohorts:
- Cohort 1—Patients with an elevated D-dimer level
- Cohort 2—Patients with an elevated D-dimer level or an age of at least 75 years
- All enrolled patients.
The statistical analysis plan specified that if the between-group difference in any of the 3 analyses was not significant, the other analyses would be considered exploratory.
In cohort 1, the primary efficacy outcome (a composite of asymptomatic proximal DVT and symptomatic VTE) occurred in 6.9% of patients receiving betrixaban and 8.5% receiving enoxaparin. The relative risk (RR) was 0.81 (95% CI, 0.65 to 1.00; P=0.054).
In cohort 2, the primary efficacy outcome occurred in 5.6% of patients receiving betrixaban and 7.1% receiving enoxaparin. The RR was 0.80 (95% CI, 0.66 to 0.98; P=0.03).
In all patients, the primary efficacy outcome occurred in 5.3% of patients receiving betrixaban and 7.0% receiving enoxaparin. The RR was 0.76 (95% CI, 0.63 to 0.92; P=0.006).
Though the differences between the treatment arms were statistically significant in the overall patient population and in cohort 2, these analyses were considered exploratory because the differences did not reach statistical significance in cohort 1.
The primary safety outcome was major bleeding. In the overall population, major bleeding occurred in 0.7% of patients receiving betrixaban and 0.6% of patients receiving enoxaparin. The RR was 1.19 (95% CI, 0.67 to 2.12; P=0.55).
The secondary safety outcome was major or clinically relevant nonmajor bleeding. It occurred in 3.1% of patients receiving betrixaban and 1.6% of patients receiving enoxaparin. The RR was 1.97 (95% CI, 1.44 to 2.68; P<0.001).
“The APEX study results show consistent evidence that VTE events can be reduced with betrixaban, with no statistical difference in major bleeding between the betrixaban and enoxaparin arms,” said study author Alexander T. Cohen, MBBS, MD, of Guy’s and St. Thomas’ Hospitals in London, UK.
“This is particularly true for the most clinically relevant symptomatic disease, where we observed a 30% to 45% reduction in events over the duration of the study. Such meaningful results in an area where there is currently no available recommended therapy offer important potential benefits for public health worldwide.”
