Study On Phase III APEX

The third phase of the betrixaban study, namely APEX, is a double-blind, double-dummy, active-controlled, multinational and randomized trial. This drug is being evaluated and assessed for its efficacy and safety as VTE prophylaxis with an extended duration in patients who hospitalized with an acute medical illness, such as respiratory failure, heart failure, rheumatoid disease, ischemic stroke, infectious disease.

Patients can follow this study if they were 40 years old or older both male or female, had been hospitalized for less than 96 hours for an acute medical illness (as defined above), and had reduced mobility and specific risk factors for venous thromboembolism. Patients were hospitalized for more than 96 hours before randomization, woman with pregnancy and breastfeeding, patients with significant clinical bleeding that occurred within the previous 6 months, had increased bleeding risk, any previous significant urogenital, pulmonary, or gastrointestinal bleed, gastritis or chronic peptic ulcer disease, endstage renal disease with creatinine clearance [CrCl] <15 mL/ min or on dialysis, history or concurrent of severe head trauma or intracranial bleed, or any trauma in the previous 3 months, aspartate transaminase (AST)/ALT >3× ULN or alkaline phosphatase >2× ULN (upper limit of normal), severe renal dysfunction and required use of a strong P-gp inhibitor, contraindications to anticoagulants, active liver disease or cirrhosis, uncontrolled HIV; concurrent or history of alcohol or drug abuse within the previous 1 year, shock requiring vasopressors or unresponsive to fluid replacement, and any history of hypersensitivity reaction to this drug were excluded from this study.

During the study period, modifications were made to the inclusion criteria for getting VTE high-risk patients. According to previous research, MAGELLAN Trial of Rivaroxaban, patients with a higher risk of VTE are patients with elevated levels of D-dimer and at least 75 years old. In addition, statistical analysis modification was carried out to get three cohorts from the entire study population. Cohort 1 subjects were patients with elevated levels of d dimer, whereas cohort 2 were patients in cohort 1 plus patients aged 75 years or older and cohort 3 included all population in the study.

For 3 years, 7513 patients were included in the inclusion criteria and randomized with an interactive voice response system, resulting in 3759 patients in the betrixaban group and 3754 patients in the enoxaparin group. Betrixaban group patients have received oral betrixaban 160 mg as a loading dose for the first time followed by 80 mg once daily for 35-42 days and once daily subcutaneous enoxaparin placebo for 6-14 days. in other hands, enoxaparin patients group received once daily enoxaparin 40 mg that administered subcutaneously for 6-14 days and once daily oral betrixaban placebo for 35-42 days. Patient with decreased renal function in enoxaparin group received a 20 mg once daily dose. In the betrixaban group, the patient with renal impairment and patients who concurrently using strong P-gp inhibitor received half of the normal dose (80 mg for loading dose and followed by 40 mg once daily dose).

The main efficacy outcome was a combination of asymptomatic or symptomatic proximal or distal DVT between day 32 and day 47, symptomatic nonfatal pulmonary embolism (PE), or death from VTE between day 1 and day 42. There are two secondary efficacy outcomes, the first is symptomatic venous thromboembolism, and the second is the main efficacy outcome with the replacements of death from VTE by death from any cause. The main safety outcome is the occurrence of major bleeding in all places up to 7 days after the cessation of all study drugs, which were classified according to criteria of the International Society on Thrombosis and Haemostasis (ISTH) as major bleeding, clinically relevant nonmajor bleeding and minimal bleeding.

In cohort 1 included patients with elevated D-dimer levels (at least a baseline of D-dimer 2xULN), the main efficacy outcome occurred in 132 of 1914 patients in the betrixaban group (6.9%) and in 166 of 1956 patients in the enoxaparin group (8,5%) with the Relative Risk (RR) in the betrixaban group 0.81, 95% Confidence Interval (CI) 0.65-1.00 and P = 0.054. The results of cohort 1 did not show any statistical significance, so all other efficacy outcomes were considered explorative and did not describe conclusions about statistical significance. In cohort 2 included patients in cohort 1 plus patients aged 75 years or older, the main efficacy outcome happened to 160 of 2842 patients in betrixaban group or about 5,6% and 204 of 2893 patients in enoxaparin group or about 7,1% with RR 0,8, 95% CI 0,66-0,98 dan P=0,03. Whereas in cohort 3, all of the population, the main efficacy outcome occurred in 5,3% patient in betrixaban group and 7,0% patients in the enoxaparin group (RR 0,76, 95% CI 0,63-0,92, P=0,006 ). The first secondary efficacy outcome (symptomatic VTE) occurred in 1,3% betrixaban group and 1,9% enoxaparin group (RR 0,67, 95% CI 0,42-1,07, P=0,09 ) (cohort 1); 1% betrixaban group and 1,4% enoxaparin group (RR 0,71, 95% CI 0,46-1,09, P=0,11 ) (cohort 2) and 0,9% betrixaban group and 1,5% enoxaparin group (RR 0,64, 95% CI 0,42-0,98, P=0,04 ) (cohort 3).

In the other hand, the second secondary efficacy outcome, i.e main efficacy outcome with the replacements of death from VTE by death from any cause happened to 11,5% betrixaban group and 12,9% enoxaparin group (RR 0,89, 95% CI 0,75-1,05, P=0,16 ) (cohort 1); 9,8% betrixaban group and 10,9% enoxaparin group (RR 0,90, 95% CI 0,77-1,04, P=0,15) (cohort 2) and 9,2% betrixaban group and 10,8% enoxaparin group (RR 0,85, 95% CI 0,73-0,98, P=0,02 ) (cohort 3). SAFETY The main safety outcome, major bleeding occurred in 0,6% betrixaban group patients and 0,7% enoxaparin group patients (RR 0,88, 95% CI 0,44-1,76, P=0,72 ) in cohort 1; 0,7% betrixaban group patients and 0,6% enoxaparin group patients (RR 1,19, 95% CI 0,66-2,11, P=0,56 ) in cohort 2, and that principal safety outcome in overall safety population happened to 0,7% betrixaban group patients and 0,6% enoxaparin group patients (RR 1,19, 95% CI 0,67-2,12, P=0,55 ).

Other safety outcomes were observed for all patients are any adverse event (54% in betrixaban group and 52% in enoxaparin group), any serious adverse event (17,7% and 16,6%), ischemic stroke (0,5% and 0,9%), other stroke (0,6% and 1,1%), died caused by bleeding (<1% in both groups), VTE (0,4% and 0,7%) and any cause (5,7% and 5,8%). Based on these results, the researchers mentioned that betrixaban in their trials was not associated with bleeding that was significantly greater than the standard duration of enoxaparin.