In the current prospective study of patients with non-valvular AF, we aimed to identify clinically relevant biomarkers that are easily accessible in clinical practice and to determine their prognostic value. The major findings were as follows: (1) RDW, creatinine, and PDW were significant biomarkers in predicting ischemic stroke during the prospective follow-up; (2) these 3 biomarkers showed higher importance than clinical risk factors in the prediction of ischemic stroke; (3) the risk of ischemic stroke was significantly higher in patients with ≥ 2 significant biomarkers than in those with < 2 significant biomarkers; (4) the addition of ≥ 2 significant biomarkers to the CHA2DS2–VASc score provided a significant improvement of the predictive ability for ischemic stroke.
New scoring systems based on biomarkers have been developed and validated. In the subanalysis of a cohort from the ENGAGE AF-TIMI 48 trial (Effective Anticoagulation with Factor Xa Next Generation in AF—Thrombolysis in Myocardial Infarction 48), incorporation of troponin I, N-terminal B-type natriuretic peptide, and D-dimer significantly enhanced the risk assessment for stroke, systemic embolic event, or death in patients with AF . In another subanalysis from the ENGAGE AF-TIMI 48 trial, the thrombolysis in myocardial infarction-AF score was demonstrated to assist in the prediction of a composite clinical outcome . Another novel scoring system—the ABC (age, biomarker, clinical history) risk score, including high-sensitivity troponin T and N-terminal B-type natriuretic peptide—was developed , and its performance was recently validated in an external cohort . Although all these scoring systems have shown the possibility of improving risk stratification in patients with AF by employing biomarkers, their application remains limited. One of the reasons might be the requirement for an additional blood test, time, and cost in real-world clinical practice. In this regard, we focused on biomarkers that can be assessed as part of routine clinical tests without additional blood sampling or cost and sought to comprehensively evaluate their efficacy to improve the current risk stratification of patients with AF. As a result, we found that RDW, creatinine, and PDW were clinically relevant in thromboembolic risk prediction in patients with AF, and that the combination of these factors can provide better predictive ability in addition to clinical risk factors. These 3 biomarkers are robust in terms of generalizability because the values of PDW and RDW are usually available in most patients undergoing routine complete blood count tests, and creatinine is also a general marker usually measured in most patients.
Although the exact mechanism should be dissected in the future studies, The prognostic value of each biomarker in patients with AF has already been suggested. RDW has been shown to be a predictor of thromboembolic events or all-cause mortality in patients with AF [14, 15]. Consistent with previous studies, we proved the predictive value of RDW for ischemic stroke among patients with AF in a prospective manner. Interestingly, RDW was the most important biomarker in the current study. Several studies seem to support the importance of RDW in patients with AF. An elevated RDW was found to be significantly associated with carotid atherosclerosis [16, 17] and was independently correlated with the presence of left atrial/left atrial appendage thrombus . One study suggested that RDW was significantly associated with poor anticoagulation control in patients with AF . Biochemically, RDW has been considered a marker of inflammation, nutritional deficiency, and oxidative stress . These studies implied that RDW represents not a single but several diverse mechanisms of ischemic stroke in patients with AF, which may partially explain the predictive value of RDW was higher than a single risk factor in the current study. The relationship between impaired renal function and increased thromboembolism risk has been well established in patients with AF [21, 22]. Its prognostic value for thromboembolic risk and cardiac mortality when added to the CHA2DS2–VASc score has been proposed . We also demonstrated the efficacy of creatinine in predicting ischemic stroke and postulated that renal function can be considered a marker for enhancing the predictive ability of the CHA2DS2–VASc score. PDW, a marker reflective of platelet activity, was also a significant biomarker, as in a previous study . One of the determinants of hypercoagulability is platelet hyperactivity, and it is associated with thrombogenesis in AF . Combined together, the 3 significant biomarkers reflect systemic inflammatory status, renal function, and hypercoagulable state, and these attributes may complement the aspect of thromboembolic risk, which cannot be reflected by the CHA2DS2–VASc score alone.
The current study had several limitations. First, a potential bias might exist because the high-risk group based on the traditional scoring system, not on biomarkers, underwent intensive medical therapy, and this could affect the incidence rate of ischemic stroke. However, we measured the biomarkers at baseline regardless of therapy, and the biomarkers could still reflect the patients’ clinical status at enrollment. Second, the cutoff of each biomarker may not be generalizable to different study populations. Despite the limitations, this study still has strengths, as it was a prospective cohort study designed only for the evaluation of simple biomarkers. Third, the number of events was not enough to postulate the linear relationship between significant biomarkers and the incidence of ischemic stroke in the current study. Therefore, future studies are warranted to validate our findings.