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Betrixaban may yet become the first new oral anticoagulant to gain approval for extended venous thromboembolism (VTE) prophylaxis in the important and underserved group of medically-ill patients, even though its pivotal trial was damaged by a self-inflicted statistical wound.

There were consistent differences in favor of betrixaban in the APEX trial and presented at the International Society on Thrombosis and Haemostasis (ISTH) meeting in Montpellier, France.

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 (RR 0.76, CI 0.63-0.92, P=0.006). 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.

The APEX trial enrolled 7,513 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.

Extended VTE prophylaxis with anticoagulants is widely accepted in high-risk patients after surgery in the hospital. Hospitalized patients with medical illnesses are also at increased risk for VTE, persisting for another month or 2, but do not now receive anticoagulation after they leave the hospital. Previous trials have failed to show the benefits of extended VTE prophylaxis in these patients.

A Big But ...

The major problem with the finding is that the overall trial analysis must be considered to be exploratory. The trial designers adopted an FDA-approved "enrichment strategy" in order to better demonstrate efficacy. There were three cohorts in the trial:

• Cohort 1, comprised of patients with an elevated D-dimer level
• Cohort 2, comprised of patients with an elevated D-dimer level and those who were at least 75 years of age
• The overall population cohort

According to the prespecified statistical plan, the investigators were required to perform a sequential analysis of the three cohorts, starting with cohort 1, then cohort 2, and then finally the overall cohort. 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 first analysis of cohort 1 just missed out on statistical significance. 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 to 1.00, P=0.054). In cohort 2, the composite outcome occurred in 7.1% and 5.6%, respectively (RR 0.80, CI 0.66-0.98, P=0.03).

"We have to be sensible when we look at the data," , of Guy's and St. Thomas' Hospitals in London and co-chair of the trial's executive committee, said in an interview. "The data is clearly showing that the event rates are decreased in the betrixaban groups." The P-value of 0.054 is the "sticking point." He said that "the level of uncertainty compared to what we normally accept is very minor."

Trial investigators and others said they think they know what went wrong with the trial. Patients were entered into cohort 1 based on local measurement of D-dimer. Subsequent analysis showed that the results would have reached significance if they had used a central lab measurement. In his interview, Cohen said the variation in test quality among different countries is the likely source of the problem.

"If we had analyzed on the centralized D-dimer we wouldn't even be talking about this and we'd be patting ourselves on the back about how clever we were," said Cohen.

Approvability

Despite the problem Cohen said that he "would be surprised" if betrixaban doesn't gain approval, though, of course, "you can never be certain." Further, because it will have no competition in the field, the drug will have "an open field" in an important market for an unmet need.

APEX is the first phase III trial for betrixaban. Cohen said he suspects that the drug may be studied for additional indications. He was encouraged by findings that showed positive outcomes for the drug in stroke and myocardial infarction patients, including a significant reduction in new ischemic strokes.

, of Cedars-Sinai in Los Angeles, said that "strictly speaking, from the perspective of null hypothesis significance testing, the primary endpoint did not make the cut." But, he continued, "for those of us that don't worship at the altar of P-value, it is the effect size and the clinical importance of the endpoints that might be more relevant."

Kaul noted that the clinically-relevant efficacy endpoints (symptomatic proximal or distal deep vein thrombosis, pulmonary embolism, and VTE-related death) ran in favor of betrixaban for all the cohorts, and the net clinical benefit also favored betrixaban.

Kaul agreed with Cohen that the investigators erred in not using central D-dimer tests. "In hindsight, this was an obvious oversight on the part of trial investigators."

Kaul also pointed out that the absolute risk difference with betrixaban is modest, but the benefit is important from both a clinical and societal perspective because the number of people at risk is so large.

I asked Cohen why he thought betrixaban had succeeded, more or less, where other oral anticoagulants, including rivaroxaban and apixaban, had failed. Cohen said it had the right pharmacology, the lowest renal clearance, a half-life of 20 hours -- making it was a true once-a-day drug -- and no CYP3A/4 interaction. "Then we enriched the whole population and we excluded a few who were at high risk of bleeding. Put simply -- the right drug, in the right population, with the right trial design."

A representative from trial sponsor Portola said the company plans to submit data from the study as part of a new drug application to the FDA in the second half of 2016. Betrixaban has received a fast-track designation from the FDA for this indication.

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