Coagulation Biomarkers and Clinical Outcomes in Elderly Patients With Nonvalvular Atrial Fibrillation

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)

However, there is a need to assess modifiable and nonmodifiable risk factors for both stroke and bleeding when initiating antithrombotic therapy. 4 Currently, the risk of stroke and bleeding in patients with AF is assessed using the CHADS 2 /CHA 2 DS 2 -VASc scores and the HAS-BLED score, respectively. 5 Performing a more personalized risk assessment for individual patients is currently challenging; however, including data on coagulation biomarkers may allow a more detailed risk assessment of stroke, bleeding, or other outcomes.
Anticoagulant therapy involves the use of direct oral anticoagulants (DOACs) and warfarin, which have different mechanisms of action. Whereas DOACs directly inhibit a single activated coagulation factor (FXa/thrombin) and have no effect on coagulation factor abundance, warfarin inhibits the biosynthesis of vitamin K-dependent coagulation factors (prothrombin, FVII, FIX, and FX), thereby reducing their levels. Furthermore, DOACs and warfarin are suggested to have different effects on coagulation markers in patients with AF. 6 Phase 3 trials of DOACs, such as the RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy), 7 ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation), [8][9][10][11] and ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-

Thrombolysis
In Myocardial Infarction 48) 12 trials, indicate that D-dimer, cardiac troponin, and Nterminal pro-B-type natriuretic peptide are predictors of stroke and mortality that significantly enhance predictive ability when added individually to clinical risk scores. However, in most of these trials, patients treated with DOACs or warfarin were not analyzed separately; instead, they were pooled together.
Currently, there is little evidence in which patients with AF receiving DOACs and those with AF receiving warfarin were separately analyzed and compared when examining the association between coagulation biomarkers and clinical outcomes. Although coagulation biomarkers may contribute to more detailed individual efficacy and safety risk assessments, 13,14 there is a dearth of data investigating the relationship between coagulation biomarkers and stroke/SEE, major bleeding, mortality, and cardiovascular (CV) events, especially in elderly patients with nonvalvular atrial fibrillation (NVAF) in a real-world setting.
We have previously reported 2-year clinical outcomes for more than 30,000 elderly patients aged $75 years with NVAF in the ANAFIE (All Nippon AF In the Elderly) Registry. 15 The objective of this subcohort study was to investigate the relationship between coagulation biomarkers and clinical outcomes in elderly Japanese patients with NVAF treated with DOACs or warfarin using the ANAFIE Registry dataset.      association was also found between low levels of TAT and F1þ2 and long-standing persistent or permanent AF, whereas no significant difference and no consistent trend was found for D-dimer and SFMC.   Table 3. Tables 1 to 3. Confounding variables included in the model are as listed in Table 3. a Not calculated due to the low number of events. Tables 1 to 3. Therefore, further analysis in a larger study would be required to confirm this result.

Abbreviations as in
In the present subcohort study, a significant association between higher D-dimer levels and all-cause death was observed. These findings are consistent with those observed in the ARISTOTLE and ENGAGE AF-TIMI 48 studies, which also reported that higher D-dimer levels were associated with an increased risk of death. 9,12 In ARISTOTLE, the benefits of apixaban compared with warfarin were consistent, regardless of the D-dimer level. 9 The relationship between D-dimer level and the incidence of stroke/SEE in this study is not consistent with studies. In the warfarin group in the present study, the outcome might be greatly influenced by the international normalized ratio control achieved during the study; this may explain why biomarker levels at the initial stage did not seem to correlate. The findings suggest that the increase in major bleeding that was observed with increasing biomarker levels may have been related to TTR. In both ARISTOTLE and ENGAGE AF-TIMI 48, higher D-dimer levels were associated with an increased incidence of stroke/SEE. Similar results were also observed in 2 studies from Japan in patients with NVAF. 13,14 However, in the present study, no association between D-dimer level and thromboembolic events was observed.
In the DOAC group of the present study, a higher Ddimer level was associated with a 2-fold increased risk for CV events and a 3.5-fold increased risk for CV death compared with lower levels of D-dimer. This is in agreement with the ARISTOTLE trial results, where higher D-dimer levels were associated with a higher rate of cardiac death. 9 In those taking DOACs, although biomarkers in the trough were associated with CV events and mortality, they were not neces-   In this study, heart failure was associated with high levels of D-dimer and a positive SFMC result. One possible explanation for this is that in patients with heart failure, stasis and endothelial dysfunction could trigger the coagulation pathway that consequently leads to fibrin formation. 26 Renal dysfunction was also associated with higher levels of D-dimer and F1þ2. Because D-dimer is excreted by the kidneys, decreased renal function may contribute to increased serum levels of D-dimer. 27,28 Renal dysfunction is

Coagulation Biomarkers and Clinical Outcomes in NVAF
A U G U S T 2 0 2 3 : 5 9 5 -6 0 7 also typically known to be associated with a state of chronic However, there may also be differences related to the mechanism of action of DOACs and the timing of blood collection (trough period); for example, the anticoagulant activity of DOACs is lowest during the trough period, 30 so it is conceivable that the level of coagulation biomarkers was increased for that reason.
Therefore, the interpretation of these results is limited because of the timing of blood collection. TRANSLATIONAL OUTLOOK: Future studies should focus on including patients of all age groups and must account for OAC changes during longer follow-up periods to assess the efficacy and safety of long-term anticoagulant therapy in patients with AF.