N‐terminal pro‐B‐type natriuretic peptide improves the predictive value of CHA2DS2‐VASc risk score for long‐term cardiovascular events in acute coronary syndrome patients with atrial fibrillation

Abstract Background It is important to identify patients with co‐morbid acute coronary syndrome (ACS) and atrial fibrillation (AF) at high risk and adopt proper management strategies to improve their prognosis. Hypothesis The addition of N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) could improve predictive value for long‐term cardiovascular events beyond the CHA2DS2‐VASc score in patients with co‐morbid ACS and AF. Methods A total of 1223 patients with baseline NT‐proBNP between January 2016 and December 2019 were included in the study. The primary endpoint was all‐cause death at 12 months. The secondary outcomes included 12‐month cardiac death and major adverse cardiovascular and cerebrovascular event (MACCE), defined as a composite of all‐cause death, myocardial infarction, or stroke. Results A higher serum of NT‐proBNP levels was strongly associated with increased risks of all‐cause death (adjusted hazard ratio [HR]: 1.05, 95% confidence interval [CI], 1.03–1.07), cardiac death (adjusted HR: 1.05, 95% CI, 1.03–1.07), and MACCE (adjusted HR: 1.04, 95% CI, 1.02–1.06). The prognostic accuracy of the CHA2DS2‐VASc score was improved when combined with NT‐proBNP to yield a 9%, 11%, and 7% increment for the discrimination of long‐term risk for all‐cause mortality (area under curve [AUC]: from 0.64 to 0.73), cardiac death (AUC: from 0.65 to 0.76), and MACCE (AUC: from 0.62 to 0.69), respectively. Conclusions In patients with ACS and AF, NT‐proBNP is a potential biomarker to enhance risk discrimination for all‐cause death, cardiac death, and MACCE in combination with the CHA2DS2‐VASc score.


| INTRODUCTION
Atrial fibrillation (AF) remains a commonly encountered complication in acute coronary syndrome (ACS) patients. 1 With a significant overlap of risk factors, concomitant AF may result in short-and longterm worse clinical outcomes in patients with ACS. 2,3 It is, therefore, important to identify individuals at high risk and adopt proper management strategies to improve their prognosis. In this regard, current guidelines recommend the use of CHA 2 DS 2 -VASc risk score for risk assessment and subsequent treatment guidance in patients with co-morbid ACS and AF. 4,5 However, the score is solely based on clinical parameters, including the presence of congestive heart failure (HF), hypertension, age, diabetes mellitus, history of stroke, vascular disease, and sex. 6 Moreover, a physician-based survey identified knowledge gaps in the application of the score for lack of a clear definition for its components. 7 For this reason, the algorithm by adding laboratory-assessed biomarkers to the CHA 2 DS 2 -VASc score might be more objective and precision to predict the risk of adverse events.
N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a nonactive prohormone that is released from the same molecule that produces BNP, mainly in response to changes in cardiac structure and function. Previous studies demonstrated a higher serum of NT-proBNP was associated with thromboembolic events and all-cause mortality in patients with ACS and/or AF. [8][9][10] However, the predictive value of combined serum NT-proBNP to CHA 2 DS 2 -T A B L E 1 Baseline characteristics according to the tertiles of NT-proBNP. Note: Data are n (%).

| Outcomes
The primary outcome was all-cause death at 12 months. The secondary outcomes included 12-month cardiac death and major adverse cardiovascular and cerebrovascular event (MACCE), defined as a composite of all-cause death, myocardial infarction, or stroke.
Clinical follow-up was performed by phone call, out-patient visit, or readmission by professional research staff at 3, 6, 9, and 12 months.
A clinical events committee examined all clinical events.

| Statistical analysis
The enrolled patients were divided based on the tertiles of

| Clinical outcomes
Follow-up at 12 months was completed in 1220 (99.7%) patients in the analysis. The principal outcomes are shown in Table 3.
Multivariable analyses showed that higher NT-proBNP levels were strongly associated with increased risks of all-cause death (   Figure 2, and Supporting Information:

| DISCUSSION
This study, using data from a large real-world registry, was designed to evaluate the serum NT-proBNP in combination with CHA 2 DS 2 -VASc score to improve risk stratification for patients with ACS and AF. The principal findings from our study are that: (1) a higher plasma NT-proBNP level at admission was associated with all-cause death, cardiac death, and MACCE after adjustment for potential confoun- and AF appeared to be strongly associated with short-and longterm mortality and thrombotic events. 3,11 Thus, it is essential to identify individuals at high risk and adopt proper therapeutic interventions to improve their prognosis. Generally, the CHA 2 DS 2 -VASc score is a simple and well-established scoring system to assess the risk of stroke and thromboembolism in patients with AF 6 and extended to predict risk for other adverse events, such as HF and AF recurrence. 12,13 However, the risk of the coronary ischemic event also need to be carefully evaluated in patients with AF and ACS. 4 The algorithm by adding biomarkers to the CHA 2 DS 2 -VASc score might be a useful tool for physicians to identify the risk of coronary ischemic events in parallel to the routine clinical risk assessment of thromboembolism. The moderate discrimination ability for mortality and cardiac adverse events prediction is shown in our analysis, which is in-agreement with a series of studies. [14][15][16] This finding highlights the need for better risk stratification models in current clinical practice. Recently, a survey by the European Heart Rhythm Association revealed the variation and uncertainty in the interpretation of components of the CHA 2 DS 2 -VASc score, especially the "C" component. 7 Honestly, guideline education and updated and unified criteria might be effective strategies to improve the accuracy in scoring the CHA 2 DS 2 -VASc score. However, it is notable that HF is by definition a clinical syndrome characterized by a series of symptoms and signs. The objective evidence for HF is also critical in diagnostic precision and treatment strategy, such as results from laboratory tests. 17 NT-proBNP is a versatile biomarker, as a non-active prohormone released from the same molecule that produces BNP. The patients with higher values of NT-proBNP are more susceptible to adverse events when compared with those with lower values. 9,18,19 In addition, some evidence suggests serum NT-proBNP could improve the predictability of risk models. [20][21][22][23] In the present study, we proved for the first time that NT-proBNP can provide additional prognostic information beyond the CHA 2 DS 2 -VASc score for all-cause death, cardiac death, and MACCE, indicating NT-proBNP as a value-added biomarker to risk stratification in patients with concomitant ACS and AF. Admittedly, the inclusion of NT-proBNP into the scoring algorithm has a potential risk to overestimate the influence of "C" element, congestive HF. However, the prognostic value of NT-proBNP is independent of heart function in AF patients. 9,24,25 T A B L E 4 Additional prognostic value provided by NT-proBNP beyond the CHA 2 DS 2 -VASc risk score. The latent mechanism might be left atrium secretion. 26 Furthermore, the concentration of NT-proBNP could support physicians to identify patients with a high risk in the absence of clinical symptoms and signs. Indeed, more studies are warranted to confirm the position of NT-proBNP in determining mortality and ischemic risk in AF patients with or without HF.
Limitations of our study should be considered. First, this is a post hoc analysis from a large prospective single-center cohort of ACS patients undergoing PCI, which may affect the generalizability of our results. Further, specific-designed studies are needed to confirm these findings. Second, the serum NT-proBNP was measured at admission before the procedure. The temporal changes of NT-proBNP might be better to predict long-term risk. However, the multiple tests of biomarkers in risk assessment need to be balanced against cost-effectiveness and complexity in routine clinical practice.
Moreover, in the present study, adding baseline NT-proBNP level to the CHA 2 DS 2 -VASc score showed a robust prognostic value to assess long-term adverse events. Finally, as with all risk-scoring algorithms, a prospective evaluation would be desirable to investigate the clinical usefulness.

| CONCLUSION
NT-proBNP is a strong risk factor for poor prognosis and enables a more accurate appreciation of risk on top of the CHA 2 DS 2 -VASc score in patients with co-morbid ACS and AF. Whether the application of a scoring system could improve the identification of high-risk patients and facilitate individualized therapeutic interventions needs further prospective evaluation.

AUTHOR CONTRIBUTIONS
Xuefei Mu and Miaohan Qiu were responsible for writing the original draft, methodology, data curation, formal analysis, and visualization.
Yi Li was responsible for conceptualization, methodology, data curation, project administration, and review editing. Ziqi Li, Bin Qi, and Zilan Jing were responsible for the investigation and review editing. Quanmin Jing was responsible for conceptualization, funding acquisition, data curation, project administration, methodology, supervision, and review editing.