Extended Betrixaban Tops Standard Enoxaparin to Stop Stroke: APEX

Marlene Busko

November 29, 2016

NEW ORLEANS, LA — Among patients hospitalized for acute medical illness, those who received the investigational new oral anticoagulant (NOAC) betrixaban (Portola) for about a month had fewer all-cause or ischemic strokes than those who received the low-molecular-weight heparin enoxaparin for a little over a week, during a 77-day follow-up, in a new study[1].

Some of the effect of this factor Xa inhibitor might be due to the extended therapy duration, the lead author and an outside expert agree. However, said the author, the study identified a group of patients at high risk of stroke in this setting that deserves more attention than current guidelines provide: those who are hospitalized for ischemic stroke or heart failure, regardless of atrial fibrillation.

Dr C Michael Gibson (Harvard Medical School, Boston, MA) presented these findings from a substudy of the Acute Medically Ill Venous Thromboembolism Prevention with Extended Duration Betrixaban (APEX) trial at an oral session at the American Heart Association (AHA) 2016 Scientific Sessions, and the results were simultaneously published in Circulation.

The study enrolled patients with heart failure (45% of patients), infection without septic shock (29%), respiratory failure (12%), stroke (11%), and rheumatic disorders (3%), he explained.

Patients who were hospitalized for heart failure or stroke were at highest risk of having a stroke, which "makes sense," but differs from thinking that only patients with atrial fibrillation have a high risk of stroke, Gibson noted.

"Is this really a comparison of the two drugs or the duration of therapy?" asked session comoderator Dr Stephen R Lentz (University of Iowa, Iowa City).

"Extended-duration prophylaxis is not part of any guidelines, so you're right; this is not just a trial of a drug but also a strategy trial," Gibson admitted. However, the Kaplan Meyer curves for all-cause stroke for patients receiving betrixaban vs enoxaparin began to diverge during the first 10 days, he noted.

Importantly, this study shows that clinicians "can identify a group of high-risk medical patients who really need more aggressive thromboprophylaxis for stroke as well as VTE," Lentz agreed, speaking to heartwire from Medscape.

"I like the drug because it has very little renal excretion, but the real exciting thing to me is that it's sort of a wake-up message that you need to realize how high-risk some of these patients are for thrombosis," he said.

Hospitalized Patients at High Risk of Stroke

Patients who are hospitalized for an acute medical illness (as opposed to surgery) and have a stroke have worse outcomes than people in the community who have a stroke, the researchers write. However, little is known about the effectiveness of prophylactic therapy with NOACs to prevent strokes in hospitalized patients.

Gibson and colleagues analyzed data from the phase 3 randomized, placebo controlled, double-dummy, double-blind APEX trial, which compared extended-duration thromboprophylaxis with betrixaban vs standard-duration enoxaparin to prevent venous thromboembolism (VTE), defined as deep vein thrombosis (DVT) and/or pulmonary embolism (PE).

APEX randomized 7513 patients who were hospitalized with acute medical illness and had an increased risk of VTE since they were immobilized, elderly, or had a positive D-dimer test, Gibson explained to heartwire .

The trial compared 40-mg/day IV enoxaparin for 10±4 days vs 80-mg/day oral betrixaban for 35 to 42 days. Patients with renal insufficiency (creatinine clearance of <30 mL/min) received half of these dosages.

In the first specified cohort—patients with an elevated D-dimer level— betrixaban reduced the incidence of VTE compared with enoxaparin, but this was not significant (P=0.054). However, betrixaban significantly reduced the incidence of VTE compared with enoxaparin in older patients with an elevated D-dimer level and in the overall population.

The current substudy of APEX aimed to compare the rate of all-cause stroke (ischemic, hemorrhagic, or unknown cause) through 77 days of follow-up (the primary efficacy outcome) and also examine the rates of transient ischemic attack (TIA) with the two types of prophylactic therapy.

There was a significant 44% reduction in relative risk of all-cause stroke and a significant 47% reduction in relative risk of ischemic stroke with betrixaban vs enoxaparin.

Risk of Stroke or TIA, Extended-Use Betrixaban vs Standard Enoxaparin

Outcome Betrixaban (n=3716),n (%) Enoxaparin (n=3716),n (%) Relative risk (95% CI) P
All-cause stroke 20 (0.54) 36 (0.97) 0.56 (0.32–0.96) 0.032
Ischemic stroke 18 (0.48) 34 (0.91) 0.53 (0.30–0.94) 0.026
All-cause stroke or TIA 24 (0.65) 41 (1.10) 0.59 (0.35–0.97) 0.034

"Although the rates of all-cause stroke appear to be low in the study [0.54% vs 0.97% for betrixaban vs enoxaparin, respectively], it must be remembered that these were 77-day crude event rates," equivalent to an annual rate of 2.55% vs 4.59%, Gibson and colleagues point out.

This is a higher annual rate of stroke than the 1.1% to 2.4% rates observed in the atrial-fibrillation population in the ROCKET-AF, ARISTOTLE, or RE-LY trials.

There were no significant differences in stroke or TIA outcomes in the subgroup of 1455 patients with renal insufficiency who received the lower doses of the two drugs, which suggests that the dosage of betrixaban "may have been excessively reduced for stroke prophylaxis," according to the authors.

Patients who were hospitalized with an index ischemic stroke had a 4.9-fold increased risk of having an all-cause stroke during follow-up (P<0.001), and those who were hospitalized for heart failure had a 2.45-increased risk of this outcome (P=0.020).

In this group of high-risk patients hospitalized with heart failure or stroke, betrixaban reduced the risk of all-cause stroke by 51% (0.72% vs 1.48%, P=0.019) and lowered the risk of ischemic stroke by 55% (0.63% vs 1.38%, P=0.014).

The number needed to treat to prevent one all-cause stroke was 233 in the whole cohort and 132 in the high-risk group.

Adding the patients with atrial fibrillation to this group of high-risk patients "didn't really magnify the benefit," said Gibson.

"Current stroke guidelines focus on atrial fibrillation, [but] this study identifies the medically ill patient [with ischemic stroke or heart failure] as one who is also at risk," he told heartwire , which is "outside the usual thinking."

Betrixaban was not associated with an increased risk of major bleeding compared with enoxaparin (0.7% vs 0.6%; P=0.55), but it was associated with a greater rate of major or clinically relevant nonmajor bleeds (3.1% vs 1.6%; P=0.03).

Fewer patients receiving extended-duration betrixaban vs standard enoxaparin had a hemorrhagic stroke, but this was not statistically significant (0.05% vs 0.19%, P=0.18)

Recent NDA for VTE Prophylaxis

"Like all factor Xa inhibitors, betrixaban will likely be developed for a broad variety of indications, including those that involve both arterial and venous disease," Gibson speculated.

On October 25, Portola submitted a new drug application (NDA) to the US Food and Drug Administration (FDA) for extended-duration betrixaban for prophylaxis to prevent VTE in acute medically ill patients, based on data from APEX. The company expects a response within 60 days as to whether the NDA is acceptable for filing.

If the FDA approves the NDA, betrixaban would be the first anticoagulant for hospital-to-home prevention of VTE in this high-risk patient population, the company says.

Betrixaban "does have attractive properties such as 7% renal clearance, which may allow it to be administered more safely in elderly patients with renal impairment," said Gibson. "It also has a long half-life of 19 hours, making once-a-day dosing feasible."

The study was funded by the sponsor Portola Pharmaceuticals. All authors received research grant support from the sponsor. Gibson received consulting income from Portola and research grant support and consulting fees from Janssen and Bayer. Disclosures for the coauthors are listed in the paper. Lentz received a research grant from Novo Nordisk, has ownership interest in Celgene, and is a consultant for Novo Nordisk and Opko.

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