Abstract
BackgroundDual therapy with a direct oral anticoagulant (DOAC) plus a P2Y12 receptor inhibitor is recommended in patients with nonvalvular atrial fibrillation who undergo percutaneous coronary intervention. Thus, we evaluated the effects of DOAC edoxaban plus P2Y12 receptor inhibitor prasugrel on bleeding time (BT), and pharmacodynamics (PD) and pharmacokinetics (PK) of edoxaban in healthy elderly Japanese male subjects.MethodsA single-center, clinical pharmacology study with randomized, open-label, repeated dosing enrolled 24 participants in two groups of 12 receiving 30 mg edoxaban once daily for 3 days; then 30 mg edoxaban plus 2.5 mg prasugrel (Group 1) or 30 mg edoxaban plus 3.75 mg prasugrel (Group 2) once daily for 5 days. Primary endpoint was BT by the Ivy method. Secondary endpoints were the PD parameters of prothrombin time (PT), activated partial thromboplastin time (aPTT), prothrombin fragment F1 + 2 (F1 + 2), and P2Y12 reaction units (PRU), and PK profiles of edoxaban alone and in combination with prasugrel.ResultsGeometric least squares mean of BT ratios (vs. baseline) for 3-day edoxaban treatment were 1.097 (90% confidence interval (CI) 0.911–1.321) in Group 1 and 1.327 (90% CI 1.035–1.703) in Group 2; for 5-day edoxaban plus 2.5 mg and 3.75 mg prasugrel, they were 1.581 (90% CI 1.197–2.087) and 1.996 (90% CI 1.482–2.690), respectively. Contributions of prasugrel to the effects (edoxaban + prasugrel/edoxaban) were 1.442 (90% CI 1.096–1.897) in Group 1 and 1.504 (90% CI 1.172–1.930) in Group 2. Edoxaban prolonged PT and aPTT and decreased F1 + 2. Adding on prasugrel did not appreciably change PT, aPTT, or F1 + 2. Prasugrel reduced PRU, whereas edoxaban had no effect on PRU. We recorded 26 adverse events; 23 were treatment-emergent (positive fecal occult blood test). All participants with adverse events recovered during follow-up.ConclusionsCoadministration of 2.5 mg and 3.75 mg prasugrel with 30 mg edoxaban prolonged BT in healthy elderly Japanese male subjects. The effect was dependent on the dose of prasugrel. Prasugrel did not affect PD or PK profiles of edoxaban. Edoxaban had no effect on PD of prasugrel.Trial registrationJapan Registry of Clinical Trials No. jRCTs071190006; registration date, 26-April-2019.
Highlights
Dual therapy with a direct oral anticoagulant (DOAC) plus a P2Y12 receptor inhibitor is recommended in patients with nonvalvular atrial fibrillation who undergo percutaneous coronary intervention
Subjects were excluded from participation in the study for any of the following reasons: presence of a bleeding disorder, prolonged bleeding time (BT) of over 9.5 min, and prolonged prothrombin time (PT) and activated partial thromboplastin time exceeding the upper limit of normal values, a positive finding in fecal occult blood test or urine occult blood test, chronic kidney disease (estimated glomerular filtration rate of less than 60 mL/min/1.73 m2), or use or consumption any of the following within 7 days before the examination: inhibitors or inducers of the drug-metabolizing enzyme CYP3A, inhibitors of P-glycoprotein, and grapefruit or any food products containing the fruit
This study provided additional, preliminary safety results that concur with the 2018 joint European consensus document [2] recommending dual-therapy use of a DOAC plus a P2Y12 receptor inhibitor and found no effect of prasugrel on PK and PD of edoxaban in healthy Japanese
Summary
Dual therapy with a direct oral anticoagulant (DOAC) plus a P2Y12 receptor inhibitor is recommended in patients with nonvalvular atrial fibrillation who undergo percutaneous coronary intervention. In patients with nonvalvular atrial fibrillation (NVAF), especially in those of advanced aged, coronary artery disease is common. In the All Nippon AF in the Elderly (ANAFIE) registry of 32,726 Japanese patients ≥75 years of age, 5600 (17.1%) had angina pectoris and 1874 (5.7%), a myocardial infarction [1]. The European Heart Rhythm Association, a branch of the European Society of Cardiology issued a 2018 joint European consensus document on the management of antithrombotic therapy in atrial fibrillation (AF) patients presenting with acute coronary syndrome and undergoing percutaneous coronary intervention (PCI) [2]. According to baseline clinical characteristics of patients taking edoxaban enrolled in the ANAFIE registry (all 75 years of age or older), 82.2% of them were taking this reduced 30 mg dose [1]
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