NEW ORLEANS – Thromboprophylaxis for 35-42 days with the new oral anticoagulant betrixaban led to a significant reduction in all-cause and ischemic strokes in medically ill patients who required hospitalization as compared with conventional prophylaxis for 10 days, based on a post-hoc analysis of data from a randomized trial with more than 7,500 patients.
But the trial’s unusual design left it unclear whether the incremental benefit seen from prolonged prophylaxis with a NOAC resulted primarily from a longer period of treatment, the drug used, or both.
The safety analysis showed that prolonged treatment with betrixaban roughly doubled the rate of major or clinically relevant nonmajor bleeding events during the period of treatment and for the first 7 days after treatment stopped. The incidence of these bleeds was 1.6% among control patients on 10 days of enoxaparin treatment and 3.1% among patients who received extended treatment with betrixaban, a statistically significant difference. The rates of fatal bleeds and intracranial hemorrhages in the two study groups did not significantly differ.
The data Dr. Gibson reported came from the Multicenter, Randomized, Active-Controlled Efficacy And Safety Study Comparing Extended Duration Betrixaban With Standard Of Care Enoxaparin For The Prevention Of Venous Thromboembolism In Acute Medically Ill Patients (). The study’s primary aim was testing in 7,513 hospitalized medically ill patients the safety and efficacy of prolonged prophylaxis with the oral, factor Xa inhibitor betrixaban, compared with 10 days of prophylaxis with the low molecular weight heparin enoxaparin. The primary endpoint was the rate of venous thromboembolic events and deaths from venous thromboembolism (VTE) out to 47 days after the start of treatment.
APEX enrolled patients hospitalized for acute decompensated heart failure, chronic respiratory failure, acute infection without septic shock, acute rheumatic disorders or acute ischemic stroke. All enrolled patients had to be expected to be immobilized for at least 24 hours following randomization and to be hospitalized for at least 3 days. Patients also had to have an additional risk marker for high thrombotic risk: They had to be at least 75 years old, or 60-74 years old with a D-dimer level at least twice the upper limit of normal, or 40-59 years old with a D-dimer level at least twice the upper limit of normal and a history of either VTE or cancer.
Results for the primary endpoint, reported in 2016, showed that prolonged betrixaban prophylaxis linked with an absolute 1.6% reduction in the combined endpoint, which resulted in a 19% relative risk reduction that fell just short of the trial’s prespecified definition of statistical significance. The study’s primary safety endpoint was the occurrence of major bleeding events through 7 days after the stop of treatment, which occurred in 0.7% of the betrixaban patients and in 0.6% of those on enoxaparin ().
Even thought the primary results from this pivotal trial failed to meet the prespecified threshold for statistical significance, the company developing betrixaban, Portola, submitted an application to the Food and Drug Administration to approve marketing of extended-duration betrixaban for VTE prophylaxis in acute medically-ill patients with VTE risk factors. In December 2016, Portolathat the FDA had given the application priority status for a decision.
The post-hoc analysis that Dr. Gibson presented at the meeting looked at the impact of betrixaban compared with enoxaparin on the incidence of all-cause and ischemic stroke during 77 days of follow-up after the start of treatment in the 7,432 patients who received at least one dose of their assigned drug, two endpoints that weren’t even secondary outcomes in APEX’s original design.
Among the 3,716 treated with betrixaban, the all-cause stroke incidence was 0.54%; among the 3,716 patients treated with enoxaparin, the all-cause stroke incidence was 0.97%. The 56% relative risk reduction was statistically significant. The incidence of ischemic strokes was 0.48% with betrixaban and 0.91% with enoxaparin, a 53% relative risk reduction that was also statistically significant.
The post-hoc analysis also looked specifically at the comparison between betrixaban and enoxaparin for stroke prevention in a subgroup of patients who had the highest stroke rate, the patients who were hospitalized because of an index stroke or an index heart failure episode. In this high-risk subgroup, prophylaxis with betrixaban cut the all-cause stroke rate compared with enoxaparin by 49% and the ischemic stroke rate by 45%, both statistically significant effects. When the high-risk subgroup also included patients hospitalized for an index episode of atrial fibrillation, betrixaban cut the rate of all-cause strokes by a relative 48% and ischemic strokes by a relative 44%.
Concurrently with Dr. Gibson’s report at the meeting, the results also appeared online (Circulation. 2016 Nov 14.).
APEX was sponsored by Portola, the company developing betrixaban. Dr. Gibson has been a consultant to Eli Lilly, Gilead, The Medicines Company, Novo Nordisk, Pfizer, and St. Jude. He has received research support from Portola and several other companies.