ENTRUST Bolsters Edoxaban As VKA Alternative In AF Patients
Executive Summary
Daiichi drug shows non-inferiority to standard antithrombotic regimen in atrial fibrillation patients, adding to evidence supporting Factor Xa inhibitor's use.
Edoxaban has met its primary endpoint of non-inferiority in bleeding in the Phase IIIb ENTRUST-AF PCI trial, a result investigators and the company said supports dual therapy with the Factor Xa inhibitor in atrial fibrillation (AF) patients receiving percutaneous coronary intervention (PCI).
The results, from what was the first large randomized, comparative study with edoxaban therapy in this setting, add to the body of evidence supporting the use of the Daiichi Sankyo Co. Ltd. drug, marketed globally as Lixiana or Savaysa.
Vitamin K antagonist (VKA)-based triple therapy is currently recommended for the 20-40% of patients with AF presenting with coronary artery disease (CAD), of whom many require revascularization via PCI and stent implantation. But triple therapy is associated with a high bleeding risk.
Results from ENTRUST-AF PCI presented to the ESC (European Society of Cardiology) Congress 2019 in Paris and simultaneously published in The Lancet showed edoxaban could be an alternative therapy to prevent bleeding and potential coronary events with an equivalent safety profile to the VKA regimen.
1,500 Patients
The open-label study enrolled 1,506 patients at 186 sites across Europe and Asia, who had successful stent placement after acute coronary syndrome (51.6%) or stable CAD (48.4%). Randomization was to once-daily oral edoxaban 60mg or 30mg plus a P2Y12 inhibitor, or VKA-based triple therapy including a P2Y12 inhibitor and 100mg acetyl salicylic acid.
Bleeding occurred in 17.0% (annualized 20.7%) of patients in the edoxaban arm versus 20.1% (annualized 25.6%) in the VKA group (HR: 0.83; 95% CI: 0.654-1.047), demonstrating non-inferiority (p=0.001, pre-specified non-inferiority margin=1.2) against the primary endpoint.
This was a composite of incidence of major or clinically relevant non-major ISTH (International Society on Thrombosis and Haemostasis)-defined bleeding over a 12-month period post-PCI.
Bleeding events were consistent across all definitions and intracranial hemorrhage occurred in 0.58% per year of edoxaban patients and 1.32% per year of VKA patients. Fatal bleeding occurred in one edoxaban patient and in seven on the VKA regimen.
There was also a trend towards less bleeding with edoxaban, but this did not reach statistical superiority (p=0.115).
Similar rates were observed in both groups against the composite efficacy outcome of cardiovascular death, stroke, systemic embolic events, spontaneous myocardial infarction and definite stent thrombosis.
"For patients with atrial fibrillation receiving PCI, an antithrombotic treatment strategy that prevents both bleeding and potential coronary events is critical," commented principal study investigator Andreas Goette, a chief physician at the St. Vincez-Hospital Paderborn in Germany.
The results support the use of the edoxaban regimen "as an alternative option with an equivalent safety profile" to VKA therapy, he said.
Daiichi Sankyo was also encouraged by the results. These "reinforce the value of the approved regimen of edoxaban" in post-PCI patients, providing potential for less bleeding without significant difference in ischemic events, said Hans Lanz, vice-president, Global Medical Affairs Specialty & Value Products.
Building Evidence, Sales
ENTRUST-AF PCI forms part of the large EDOSURE suite of randomized and real world evidence studies designed to generate additional data to support the use of edoxaban in various AF and venous thromboembolism settings and patient groups, and involving more than 100,000 patients in total.
Following the genericization of former blockbuster olmesartan (sold as Benicar and others), the Factor Xa inhibitor has become Daiichi Sankyo's largest product globally, and the company expects it to sell JPY149bn ($1.39bn; +27%) in the fiscal year to next April.
Datamonitor Healthcare forecasts sales in the US, Japan and five major European markets will rise to $842.5m in the stroke prevention in atrial fibrillation setting in 2026.
Ongoing development work includes a Phase III trial in Japan for patients aged 80+ with non-valvular AF, for which an approval is anticipated in 2021.