Betrixaban for VTE Prevention in the Medically Ill Population,the APEX Trial: Good News for This Needy Population?

Venous thromboembolism (VTE) prevention in the medically ill population is still a big issue. The majority of patients in a hospital are medically ill, and the majority of deep venous thrombosis and pulmonary embolism in hospital come from this nonsurgical population. ¹ The standard of care for chemoprophylaxis for this population are low-molecular-weight heparins (LMWHs; mainly enoxaparin, based on the prophylaxis in MEDical patients with ENOXaparin [MEDEDNOX] trial) or fondaparinux (based on the Arixtra for the prevention of Thromboembolism in medically ill patients [ARTEMIS] trial). Both parenteral compounds are very effective, providing relative risk reductions (RRRs) around 50% when compared to placebo in these above-mentioned trials. However, they were designed to be used as in-hospital agents. Half of VTEs in the medically ill patients happen around 30 days after discharge. And these injectable compounds failed to prove efficacy in protecting patients in the out-of-hospital setting, due to increased risk of bleeding. ²

Non–vitamin K oral anticoagulants (NOACs) were designed for stroke prevention in nonvalvular atrial fibrillation for a very fragile population and seemed to be very effective and safe. It was a no-brainer decision to test them on the medically ill population for a prolonged period of time (30 days), compared to the standard of care therapy, the in-hospital LMWHs. Dabigatran was never tested in this population. On the Multicenter, rAndomized, parallel Group Efficacy and safety study for the prevention of VTE in hospitalized medically iLL patients comparing rivaroxabAN with enoxaparin (MAGELLAN) trial, rivaroxaban showed 23% RRR in VTE events, achieving the prespecified superiority end point for efficacy but failed to prevent increase in bleeding. ³ On the Apixaban Dose Optimized for the prevention of thrombosis-related events in patients with acute medical illness (ADOPT) trial, apixaban failed to show superiority for efficacy (13% RRR, underpowered trial) and led to an increase in bleeding. ⁴ Lesson learned from the MAGELLAN trial showed that the population with high D-dimer levels might benefit from this prolonged treatment with NOACs. ⁵

The Acute Medically Ill Venous Thromboembolism Prevention with Extended Duration Betrixaban (APEX) study trial, which compared betrixaban 80 mg every day to the in-hospital standard of care enoxaparin 40 mg every day and was recently reported at the New England Journal of Medicine, ⁶ was designed with the lessons learned from both MAGELLAN and ADOPT trials. The APEX trial enrolled 7513 hospitalized patients with an acute medical illness who were immobile and had risk factors for VTE. Patients were randomized to either enoxaparin (Lovenox) or betrixaban for 7 to 10 days. Enoxaparin patients then received placebo, and betrixaban patients continued their treatment for another 35 to 42 days.

In the overall population, the primary efficacy outcome (a composite of asymptomatic proximal deep vein thrombosis and symptomatic VTE) was reduced from 7% in the control group to 5.3% in the betrixaban group (relative risk [RR]: 0.76, confidence interval [CI]: 0.63-0.92; P = .006). There was no significant difference between the groups in the primary safety measure—major bleeding, which occurred in 0.6% of the control group and 0.7% of the betrixaban group.

Looking at the overall population, the trial looks positive. However, the major drawback with the finding of the APEX is that the overall trial analysis must be considered to be exploratory. The trial was designed to incorporate an Food and Drug Administration (FDA)-approved “enrichment strategy” in order to better demonstrate efficacy. There were 3 cohorts in the trial:

Cohort 1—consisting of patients with an elevated D-dimer level (2 times the upper normal limit),

Cohort 2—comprised of patients with an elevated D-dimer level and those who were aged at least 75 years, and

Cohort 3—the overall population.

Cohort 1 failed to show superiority of betrixaban versus the standard of care. The primary efficacy outcome occurred in 8.5% of the control group and 6.9% of the betrixaban group (RR: 0.81, CI: 0.66-1.00; P = .054). It is a tricky result—had only 1 patient presented an event on the other side and the cohort would have been positive. The upper limit of the confidence interval just touched 1, yielding a P value of .054.

In cohort 2, the composite outcome occurred in 7.1% and 5.6%, respectively (RR: 0.80, CI: 0.66-0.98; P = .03). Cohort 3, the overall population, also lead to a positive result, with rates of 5.3% and 7.0% (RR: 0.76; 95% CI: 0.63-0.92; P = .006), respectively.

According to the prespecified hierarchical statistical plan, a sequential analysis of the 3 cohorts, starting with cohort 1, then cohort 2, and then finally, the overall population cohort (cohort 3), was supposed to be performed. The statistical plan specified that if the between-group difference in any analysis in this sequence was not significant, the other analyses were considered to be exploratory. The trialists who conducted the APEX trial believe that this statistical flaw happened because of the local laboratory analysis for D-dimers. A central laboratory analysis showed that even cohort 1 would have been positive. From a purist, statistical standpoint, the trial failed to prove superiority on the primary end point. From a medical standpoint, it is a positive trial. The PDUFA date for betrixaban is planned for the second half of 2016. Betrixaban has a fast-track application with the FDA for this particular indication. It is expected that betrixaban gets its approval from the FDA, but given the results on cohort 1, there is still uncertainty if an NOAC will finally have an indication for the VTE prevention in the medically ill population.