Daiichi Sankyo Presents Positive Results from LIXIANA Study

Daiichi Sankyo announced results from ENTRUST-AF PCI, the first large randomized study to evaluate the efficacy and safety of once-daily edoxaban (known by the brand name LIXIANA®▼) plus a P2Y12 inhibitor against a regimen of vitamin K antagonist (VKA) plus P2Y12 inhibitor and acetyl salicylic acid (ASA) in atrial fibrillation (AF) patients following successful percutaneous coronary intervention (PCI). The study showed the edoxaban-based regimen is non-inferior compared with the VKA-based triple therapy regimen on the composite endpoint of major or clinically-relevant non-major bleeding over 12 months.

It is estimated that about 20% to 40% of patients with AF also present with coronary artery disease (CAD), a sizeable proportion of whom requires revascularization using percutaneous coronary intervention (PCI) and stent implantation. Current treatment guidelines for these patients recommend VKA-based triple therapy including a P2Y12 inhibitor and ASA, however, triple therapy has been associated with significantly increased risk of bleeding. ENTRUST-AF PCI was a multinational, multicenter, randomized, open-label, blinded outcome evaluation Phase 3b study that evaluated a 12-month antithrombotic regimen of edoxaban 60 mg once-daily in combination with a P2Y12 inhibitor compared to a VKA in combination with a P2Y12 inhibitor and 100 mg of ASA for a risk adapted duration for one to 12 months in patients with AF following successful stent placement for ACS or stable CAD. The primary safety outcome was the composite of major or clinically relevant non-major bleeding, as defined by the International Society of Thrombosis and Haemostasis (ISTH).

"For patients with atrial fibrillation receiving PCI, an antithrombotic treatment strategy that prevents both bleeding and potential coronary events is critical," said Andreas Goette, MD, Chief Physician, St. Vincez-Hospital Paderborn, Germany, Department of Cardiology and Intensive Care Medicine and principal study investigator. "These results from the ENTRUST-AF PCI study support the use of a dual antithrombotic therapy with edoxaban plus a P2Y12 inhibitor as an alternative option with an equivalent safety profile compared to VKA-based triple therapy, including a P2Y12 inhibitor, plus risk adapted ASA for a duration of one to 12 months."

The ENTRUST-AF PCI study enrolled 1,506 patients with AF following successful stent placement for ACS (51.6%) or stable CAD (48.4%). Patients were randomized to receive once-daily edoxaban (60 mg or 30 mg per dose reduction criteria) plus a P2Y12 inhibitor for 12 months or a VKA in combination with a P2Y12 inhibitor plus 100 mg of ASA.[1] Major or clinically relevant non-major bleeding, the study's primary endpoint, occurred in 128 (17.0%; annualized: 20.7%) patients in the edoxaban group and 152 (20.1%; annualised: 25.6%) patients in the VKA group (HR: 0.83, 95% CI: 0.654-1.047), demonstrating non-inferiority of the edoxaban-based dual therapy for the 12 months post PCI (p=0.001, pre-specific non-inferiority margin=1.2). There was a trend toward less bleeding with edoxaban, though, results did not show statistical superiority (p=0.115). Similar rates of the main efficacy composite outcome of cardiovascular death, stroke, systemic embolic events, spontaneous myocardial infarction, and definite stent thrombosis were observed for the edoxaban-based dual therapy regimen and the VKA-based triple therapy regimen.

"These results reinforce the value of the approved regimen of edoxaban for AF treatment in post-PCI patients, providing the potential for less bleeding compared to current standard-of-care VKA-based triple therapies without significant differences in ischemic events," said Hans Lanz, MD, Vice President, Global Medical Affairs Specialty & Value Products, Daiichi Sankyo. "ENTRUST-AF PCI is part of the Edoxaban Clinical Research Program, which is designed to address a broad range of cardiovascular conditions and patient types including the elderly. We are encouraged by these results which represent an important advancement in our understanding of how to best manage AF patients post-PCI."

In the ENTRUST-AF PCI study, bleeding events were consistent across all commonly applied bleeding definitions (ISTH, TIMI, BARC). Intracranial hemorrhage occurred in four (0.58% per year) of edoxaban-treated patients and nine (1.32% per year) VKA-treated patients. Fatal bleeding occurred in one patient receiving edoxaban and seven patients receiving VKA treatment.

ENTRUST-AF PCI is one of more than 10 randomized, controlled trials (RCTs), registries and non-randomized clinical studies that comprise the Edoxaban Clinical Research Programme. More than 100,000 patients worldwide are expected to participate in the Edoxaban Clinical Research Programme studies, with the goal of generating new clinical and real-world data regarding edoxaban use in AF and venous thromboembolism (VTE) populations, providing physicians and patients worldwide with greater treatment confidence.

EdoxabaN TReatment VersUS Vitamin K Antagonist in PaTients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention (ENTRUST-AF PCI) is a prospective, multinational, multicenter, randomised, open-label with blinded endpoint evaluation phase 3b study. The ENTRUST-AF PCI trial was designed to evaluate the safety and accrue exploratory information on the efficacy of an edoxaban-based antithrombotic regimen compared to a VKA-based antithrombotic regimen in patients with AF following successful PCI with stent implantation. The primary objective of the ENTRUST-AF PCI trial was to compare the incidence of major or clinically relevant non-major International Society on Thrombosis and Haemostasis (ISTH)-defined bleeding over a 12-month period of an edoxaban-based antithrombotic regimen against a VKA-based regimen. 1,506 patients were enrolled in ENTRUST-AF PCI from 186 clinical sites across Europe and Asia. Participants were randomly allocated in a 1:1 ratio to a 12-month antithrombotic regimen of edoxaban and a P2Y12 inhibitor or to a standard therapy with a vitamin K antagonist (VKA) and P2Y12 inhibitor plus ASA for one to 12 months.

AF is a condition where the heart beats irregularly and rapidly. When this happens, blood can pool and thicken in the chambers of the heart causing an increased risk of blood clots. These blood clots can break off and travel through the blood stream to the brain (or sometimes to another part of the body), where they have the potential to cause a stroke.

AF is the most common type of heart rhythm disorder and is associated with substantial morbidity and mortality. More than six million Europeans are diagnosed with AF, and this figure is expected to at least double over the next 50 years. Compared to those without AF, people with the arrhythmia have a 3-5 times higher risk of stroke. One in five of all strokes are a result of AF.

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