APEX Trial Misses Primary Outcome, but Betrixaban May Still Lower VTE in Acutely Ill

Deborah Brauser

June 07, 2016

LONDON, UK — Although its trial setup may have caused complications, new research suggests that the new oral anticoagulant (NOAC) betrixaban (Portola Pharmaceuticals) may still be helpful in reducing venous thromboembolism (VTE) in hospitalized patients[1].

The phase 3 Acute Medically Ill VTE Prevention With Extended-Duration Betrixaban (APEX) study of more than 7500 participants showed that the primary efficacy outcome of combined proximal deep-vein thrombosis and symptomatic VTE just missed significance between those receiving oral betrixaban for 35 to 42 days vs those receiving 10 days of subcutaneous enoxaparin (6.9% vs 8.5%, respectively, P=0.054) in the prespecified first cohort—which examined just those with elevated D-dimer levels.

On the other hand, analyses of cohort 2 (those with elevated D-dimer levels or older than 74 years) and of the entire patient population did show significantly fewer events in the betrixaban- vs enoxaparin-receiving groups (5.6% vs 7.1%, P=0.03 and 5.3% vs 7.0%, P=0.006; respectively).

However, because of APEX's prespecified setup, all analyses occurring after cohort 1 were considered exploratory.

Still, lead investigator Dr Alexander T Cohen (Guy's and St Thomas' Hospitals, London, UK) pointed out to heartwire from Medscape that the number of participants was higher in both cohort 2 and the overall population and relative risk reduction was greater in both.

"We mistakenly chose to look at local D-dimer tests" in the first cohort, with test quality varying among the countries involved, instead of central D-dimer, "which is a more significant test," explained Cohen. He noted that when further analysis looked just at central lab measurements, the primary outcome was "extremely" significantly lower in the betrixaban group.

In addition, he noted that Portola hopes to submit a new drug application (NDA), including these trial data, to the US Food and Drug Administration (FDA) soon.

"I think anyone with any common sense would see that the first cut had the smaller sample size and used the least specific measurement. And most people would say it's just a bit of bad luck," said Cohen.

"The FDA has been very clear with us that we can continue with applying for an NDA. We'll have to see what they say but I'm confident that this drug will be approved despite the 0.054 finding."

The APEX results were published online May 27, 2016 in the New England Journal of Medicine.

Relative Risk

APEX included 7513 patients hospitalized at sites in 35 countries between March 2012 and November 2015 for acute illnesses, such as heart failure, respiratory failure, and ischemic stroke. All were at least 40 years of age.

Of these participants, 3759 were randomly assigned to a subcutaneous enoxaparin placebo for 10+4 days, as well as 80 mg daily of oral betrixaban for 35 to 42 days (betrixaban group; 55% women; mean age 76.6 years); 3754 were assigned to 40 mg daily of subcutaneous enoxaparin plus an oral betrixaban placebo (enoxaparin group; 54% women; mean age 76.2 years).

The researchers then examined outcomes in "three prespecified, progressively inclusive cohorts." Cohort 1 included 3870 participants with D-dimer levels at least twice the upper limit of the normal range, cohort 2 included these patients plus those who were at least 75 years of age (n=5735), and cohort 3 included the overall population.

"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," report the investigators.

The relative risk (RR) in cohort 1 for the primary composite efficacy outcome was 0.81 in the betrixaban group (95% CI 0.65–1.00). In cohort 2 the RR was 0.80 (95% CI 0.66–0.98); and in cohort 3 the RR was 0.76 (95% CI 0.63–0.92).

"Convincing Data"

In the overall population, the secondary end point of symptomatic VTE occurred in significantly fewer of the betrixaban group compared with the enoxaparin group (0.9% vs 1.5%, respectively; P=0.04).

There were no significant differences in major bleeding rates—the principal safety outcome—between those receiving betrixaban (0.7%) and those receiving enoxaparin (0.6%; RR 1.19, 95% CI 0.67–2.12). The betrixaban group did have more nonmajor bleeding events (3.1% vs 1.6%, respectively).

On the other hand, the betrixaban group had lower rates of new ischemic strokes (0.5% vs 0.9%, respectively, P=0.03) and strokes of all types (0.6% vs 1.1%, P=0.03).

The net clinical benefit for the overall population, a composite of any component of the primary efficacy outcome or principal safety outcome, was 5.8% in those receiving betrixaban and 7.3% in those receiving enoxaparin (P=0.01).

"It would be very sad if [betrixaban] didn't get approved because there are tens of thousands of lives lost every year because we haven't got an agent in this area," said Cohen. "I think we have convincing data, and it would be a tragedy if it doesn't go through."

The study was funded by Portola Pharmaceuticals. Cohen reports personal fees from Portola Pharmaceuticals during the conduct of the study; grant support and personal fees from Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo; and personal fees from Boehringer Ingelheim, Johnson & Johnson, Sanofi, XO1, Janssen, and Bayer HealthCare. Disclosures for the coauthors are listed in the article.

Follow Deborah Brauser on Twitter: @heartwireDeb. For more from theheart.org, follow us on Twitter and Facebook.

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