Effects of concomitant use of prasugrel with edoxaban on bleeding time, pharmacodynamics, and pharmacokinetics of edoxaban in healthy elderly Japanese male subjects: a clinical pharmacology study

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]. The document recommends as short a period as possible for triple therapy with an oral anticoagulant plus dual antiplatelet agents (a P2Y₁₂ receptor inhibitor and aspirin), followed by dual therapy with an oral anticoagulant plus a single antiplatelet agent (P2Y₁₂ receptor inhibitor).

The direct oral anticoagulant (DOAC) used in our study was edoxaban, a direct inhibitor of activated blood coagulation factor X, indicated to reduce the risk of stroke and systemic embolism in patients with NVAF [3, 4]. Edoxaban is available in a standard dose of 60 mg and a reduced dose of 30 mg for patients with low body weight (≤60 kg), moderate or severe renal impairment (creatinine clearance 15–50 mL/min), or concomitant use of potent P-glycoprotein inhibitors [4, 5]. 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].

The P2Y₁₂ receptor inhibitor administered with edoxaban in this study was prasugrel, indicated for patients with acute coronary syndrome, stable angina, or old myocardial infarction who are to be managed with PCI in Japan [6, 7]. Compared to clopidogrel, prasugrel is a more potent P2Y₁₂ receptor inhibitor [6‐9]. In Japan, the doses of prasugrel (loading dose, 20 mg; standard daily maintenance dose, 3.75 mg; reduced daily maintenance dose, 2.5 mg for patients with low body weight ≤ 50 kg) are lower than those approved in western countries (loading dose, 60 mg; daily maintenance dose, 10 mg), and the bleeding risk of prasugrel was shown to be similar to that of clopidogrel [8, 9]. Recently, a retrospective analysis of an observational cohort study reported that in Japanese AF patients undergoing PCI, prasugrel as a part of triple therapy with aspirin and an oral anticoagulant had not increased the risk of bleeding compared to clopidogrel [10]. Besides this observational study, a phase 3b trial [11] was conducted to analyze the safety of edoxaban in combination with a P2Y₁₂ receptor inhibitor in AF patients undergoing PCI. The study demonstrated that edoxaban plus a P2Y₁₂ receptor inhibitor was non-inferior for bleeding events compared with a vitamin K antagonist in combination with a P2Y₁₂ receptor inhibitor and aspirin without significant differences in ischemic events. However, data on the combination of edoxaban and prasugrel are very limited.

Here, we aimed to assess the effects of edoxaban plus prasugrel on bleeding time (BT), and pharmacodynamic (PD) and pharmacokinetic (PK) profiles of edoxaban in healthy elderly Japanese male subjects between the ages of 65 and 80.

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 also found no effect of prasugrel on PK and PD of edoxaban in healthy Japanese male subjects of normal weight (50 to 60 kg; BMI 21.1 ± 1.6 kg/m²) and advanced age (65 to 80 years).

Results of BT measured by the Ivy method were predictable and confirmatory for coadministration of edoxaban with prasugrel. Edoxaban (30 mg) alone prolonged BT 1.10- or 1.33-fold from baseline, and the addition of 2.5 mg and 3.75 mg prasugrel to edoxaban further prolonged BT 1.58- or 2.00-fold, respectively. The effect of prasugrel on BT was dose-dependent. This two-fold increase was comparable to the coadministration of 60 mg edoxaban with aspirin or naproxen, antiplatelet agents used in the study of Mendell et al. [13] and less than a 3.8-fold increase after the coadministration of 15 mg rivaroxaban with standard doses of clopidogrel [14]. The incidence of bleeding events caused by the concomitant treatment with 60 mg edoxaban plus aspirin has been evaluated in patients with peripheral artery disease who have undergone endovascular treatment [15]. The bleeding risk of 60 mg edoxaban plus aspirin was similar to that of standard dual antiplatelet therapy with clopidogrel plus aspirin [15]. Another clinical study showed that concomitant use of 15 mg rivaroxaban with clopidogrel in NVAF patients undergoing PCI was associated with a lower rate of clinically significant bleeding when compared to standard therapy with a vitamin K antagonist plus dual antiplatelet therapy [16]. Although BT may not always be correlated with bleeding risk in patients receiving antithrombotic agents [17, 18], the present data suggest that bleeding risk by dual-therapy edoxaban and prasugrel might be low.

The results of PD and PK parameters were also predictable and confirmatory. As expected, edoxaban alone prolonged PT and aPTT and decreased F1 + 2. Combined treatment with prasugrel had no additional effect on these parameters. In terms of platelet function, edoxaban alone had no effect on platelet aggregation, and only after administration of prasugrel, platelet aggregation was suppressed. Coadministration of prasugrel with edoxaban did not affect the PK parameters of edoxaban. These results of the combined administration of DOAC edoxaban and P2Y₁₂ receptor inhibitor prasugrel are consistent with those reported previously for rivaroxaban and clopidogrel [14]; clopidogrel did not alter the anticoagulant effects and PK of rivaroxaban, whereas platelet aggregation was not affected by rivaroxaban.

This study reports safety results on the coadministration of edoxaban with prasugrel in a small study. All the treatment-emergent AEs were non-serious AEs. Most of the AEs were a positive fecal occult blood test, and all subjects with this AE did not require any treatment during the study period. Additionally, no study withdrawal or discontinuation due to AEs were observed.

It is also important to note that the reduced dose of edoxaban (30 mg) is used in 82% of elderly (≥75 years of age) AF patients in Japan [1]. Thus, for elderly AF patients undergoing PCI, clinicians can consider giving the reduced 30 mg dose of edoxaban with either the 2.5 mg or 3.75 mg dose of prasugrel. Since the effect of prasugrel on BT was dose-dependent, 2.5 mg prasugrel would be an option for patients whose body weight is ≤50 kg or who have other risk factors for bleeding.

There are several limitations of the study. First, this is a small clinical pharmacology study of short-term treatment in healthy elderly Japanese male subjects. Although we have set the duration of treatment for the purpose of reaching the steady states of PK variables for both edoxaban and prasugrel, according to the European consensus document [2] up to 12 months of treatment of dual therapy with an oral anticoagulant plus a P2Y₁₂ receptor inhibitor are required for AF patients undergoing PCI. Large clinical studies are required to assess the concomitant use of edoxaban and prasugrel over a longer period in these patients, especially in patients who are at high-risk for bleeding. Second, it would be hard to predict bleeding risk of antithrombotic agents by BT results only [17, 18]. However, BT is currently the only method used to assess the risk of bleeding in clinical pharmacological studies of antithrombotic agents or combined effects of anticoagulant and antiplatelet agents [13, 14]. The increase in BT in a clinical study may indicate a potential for a higher risk of bleeding.

Coadministration of the P2Y₁₂ receptor inhibitor 2.5 mg and 3.75 mg prasugrel with the DOAC 30 mg edoxaban prolonged BT in healthy elderly Japanese male subjects. The BT prolongation was dependent on the dose of prasugrel. Prasugrel did not affect PD or PK parameters of edoxaban.