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. 2023 Aug 15;3(4):595-607.
doi: 10.1016/j.jacasi.2023.06.004. eCollection 2023 Aug.

Coagulation Biomarkers and Clinical Outcomes in Elderly Patients With Nonvalvular Atrial Fibrillation: ANAFIE Subcohort Study

Yukihiro Koretsune  1 , Takeshi Yamashita  2 , Masaharu Akao  3 , Hirotsugu Atarashi  4 , Takanori Ikeda  5 , Ken Okumura  6 , Wataru Shimizu  2 , Shinya Suzuki  7 , Hiroyuki Tsutsui  8 , Kazunori Toyoda  9 , Atsushi Hirayama  10 , Masahiro Yasaka  11 , Takenori Yamaguchi  9 , Satoshi Teramukai  12 , Tetsuya Kimura  13 , Yoshiyuki Morishima  13 , Atsushi Takita  14 , Hiroshi Inoue  15
Affiliations

Coagulation Biomarkers and Clinical Outcomes in Elderly Patients With Nonvalvular Atrial Fibrillation: ANAFIE Subcohort Study

Yukihiro Koretsune et al. JACC Asia. .

Abstract

Background: Little is known about the relationship between coagulation biomarkers and clinical outcomes in patients with atrial fibrillation (AF) treated with anticoagulants, especially direct oral anticoagulants (DOACs) and warfarin.

Objectives: This subcohort study evaluated the association between coagulation biomarkers and clinical outcomes in elderly Japanese patients with nonvalvular AF using the ANAFIE (All Nippon AF In the Elderly) Registry.

Methods: Patients with a definitive diagnosis of nonvalvular AF and aged ≥75 years at enrollment were included. At enrollment, biomarker levels for D-dimer, thrombin-antithrombin complex (TAT), prothrombin fragment 1+2 (F1+2), and soluble fibrin monomer complex (SFMC), along with data on anticoagulant use, were recorded.

Results: Of the 3,194 patients, 95.1% were using oral anticoagulants (OACs) (71.7% DOACs, 23.4% warfarin). D-dimer, TAT, and F1+2 levels, as well as the proportion of patients with a positive SFMC, were lower among those receiving OACs compared with those not receiving OACs. In the DOAC group, higher levels of D-dimer (≥1.0 μg/mL) and TAT (>3 ng/mL) were significantly associated with increased incidences of cardiovascular (CV) events (stroke, myocardial infarction, cardiac intervention, heart failure, and CV death), all-cause death, and CV death. In the warfarin group, higher levels of D-dimer were significantly associated with increased rates of all-cause death, higher levels of TAT with increased major bleeding, and positive SFMC with increased major bleeding and CV events.

Conclusions: Higher levels of coagulation biomarkers were associated with a higher risk of worse clinical outcomes, and the relationships between the coagulation biomarkers and outcomes differed between the DOAC and warfarin groups. (Prospective Observational Study in Late-Stage Elderly Patients with Non-Valvular Atrial Fibrillation All Nippon AF In Elderly Registry-ANAFIE Registry; UMIN000024006).

Keywords: D-dimer; all-cause death; coagulation biomarker; prothrombin; stroke; systemic embolic events.

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Conflict of interest statement

This research was supported by Daiichi Sankyo Co, Ltd. Dr Koretsune has received remuneration from Daiichi Sankyo, Bristol Myers Squibb, and Nippon Boehringer Ingelheim. Dr Yamashita has received research funding from Bristol Myers Squibb, Bayer, and Daiichi Sankyo; manuscript fees from Daiichi Sankyo and Bristol Myers Squibb; and remuneration from Daiichi Sankyo, Bayer, Pfizer Japan, and Bristol Myers Squibb. Dr Akao has received research funding from Bayer and Daiichi Sankyo; and remuneration from Bristol Myers Squibb, Nippon Boehringer Ingelheim, Bayer, and Daiichi Sankyo. Dr Atarashi has received remuneration from Daiichi Sankyo. Dr Ikeda has received research funding from Daiichi Sankyo and Bayer; and remuneration from Daiichi Sankyo, Bayer, and Pfizer Japan. Dr Okumura has received remuneration from Nippon Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, and Medtronic. Dr Shimizu has received research funding from Bristol Myers Squibb, Daiichi Sankyo, and Nippon Boehringer Ingelheim; and remuneration from Daiichi Sankyo, Pfizer Japan, Bristol Myers Squibb, Bayer, and Nippon Boehringer Ingelheim. Dr Suzuki has received research funding from Mitsubishi-Tanabe and Daiichi Sankyo; and remuneration from Bristol Myers Squibb and Daiichi Sankyo. Dr Tsutsui has received research funding from Daiichi Sankyo and Nippon Boehringer Ingelheim; remuneration from Daiichi Sankyo, Bayer, Nippon Boehringer Ingelheim, and Pfizer Japan; scholarship funding from Daiichi Sankyo; and consultancy fees from Pfizer Japan, Bayer, and Nippon Boehringer Ingelheim. Dr Toyoda has received lecture honoraria from Daiichi-Sankyo, Otsuka, Novartis, Abbott, Bayer, and Bristol Myers Squibb outside the submitted work. Dr Hirayama has participated in a course endowed by Boston Scientific Japan; has received research funding from Daiichi Sankyo and Bayer; and remuneration from Bayer, Daiichi Sankyo, Bristol Myers Squibb, and Nippon Boehringer Ingelheim. Dr Yasaka has received research funding from Nippon Boehringer Ingelheim; and remuneration from Nippon Boehringer Ingelheim, Daiichi Sankyo, Bayer, Bristol Myers Squibb, and Pfizer Japan. Dr Yamaguchi has acted as an Advisory Board member of Daiichi Sanky;o and received remuneration from Daiichi Sankyo and Bristol Myers Squibb. Dr Teramuki has received research funding from Nippon Boehringer Ingelheim; and remuneration from Daiichi Sankyo, Sanofi, Takeda, Chugai Pharmaceutical, Solasia Pharma, Bayer, Sysmex, Nipro, NapaJen Pharma, Gunze, Kaneka, Kringle Pharma, and Atworking. Drs Kimura, Morishima, and Takita are employees of Daiichi Sankyo. Dr Inoue has received remuneration from Daiichi Sankyo, and Bristol Myers Squibb; and consultancy fees from Daiichi Sankyo. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

None
Graphical abstract
Central Illustration
Central Illustration
Summary of Biomarker Levels According to Anticoagulant Used Median (Q1, Q3) biomarker levels and the distribution of patients at enrollment according to the usage of anticoagulants for the biomarker categories are shown. Blood was collected at enrollment and biomarker levels were determined. P values were calculated using the chi square test for categorical variables, and analysis of variance for continuous variables. Significantly higher levels of D-dimer, TAT, and F1+2 were observed among patients who were not receiving anticoagulants compared with patients receiving DOACs or warfarin. The likelihood of having positive SFMC was higher for patients either not receiving OACs or receiving DOACs vs patients receiving warfarin. DOAC treatment resulted in higher levels of D-dimer and F1+2 versus warfarin treatment. DOAC = direct oral anticoagulant; F1+2 = prothrombin fragment 1+2; OAC = oral anticoagulant; Q = quartile; SFMC = soluble fibrin monomer complex; TAT = thrombin–antithrombin complex; WF = warfarin.
Figure 1
Figure 1
Comparison Between DOAC and Warfarin for Outcomes by Biomarkers The forest plots show (A) D-dimer, (B) TAT, (C) F1+2, and (D) SFMC. DOAC = direct oral anticoagulant; F1+2 = prothrombin fragment 1+2; SFMC = soluble fibrin monomer complex; SEE = systemic embolic events; TAT = thrombin–antithrombin complex.
Figure 1
Figure 1
Comparison Between DOAC and Warfarin for Outcomes by Biomarkers The forest plots show (A) D-dimer, (B) TAT, (C) F1+2, and (D) SFMC. DOAC = direct oral anticoagulant; F1+2 = prothrombin fragment 1+2; SFMC = soluble fibrin monomer complex; SEE = systemic embolic events; TAT = thrombin–antithrombin complex.
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