Patients and methods: Between January 2016 and December 2020, a total of 423 AF patients (183 males, 240 females; mean age: 73.4±5.8 years; range, 65 to 89 years) were retrospectively analyzed. The patients were divided into two groups according to the Controlling Nutritional Status (CONUT) score: ≥5 (n=92) and <5 (n=331). All patients were followed for at least two years from the first presentation.

Results: Major bleeding and mortality were found to be higher in the CONUT score ≥5 group (8.7% vs. 3.0%, p=0.017 and 18.5% vs. 10.0%, p=0.025, respectively). While there was higher major bleeding and mortality in CONUT ≥5 patients using warfarin, there was no significant difference in the DOAC group (warfarin p=0.009, DOAC p=0.337 and warfarin p=0.046, DOAC p=0.171, respectively). In the receiver operating characteristic analysis, a cut-off value of 3.5 of the CONUT score predicted both mortality and major bleeding (area under the curve [AUC]: 0.781, p<0.001 and AUC: 0.733, p=0.001, respectively).

Conclusion: According to the CONUT score, a higher rate of major bleeding and mortality was found in AF patients aged 65 and over with moderate-severe malnutrition. Based on these findings, the use of DOAC may be more reliable in this patient group.

The Controlling Nutritional Status (CONUT) score is an objective method that can be easily calculated from patients' laboratory data, such as albumin, total cholesterol and lymphocyte count, and indicates nutritional status.[8] Previous studies have shown that the CONUT score is useful for predicting prognosis in patients with coronary artery disease, heart failure, and transcatheter aortic valve implantation.[9-11] In a study conducted including patients hospitalized due to novel coronavirus disease 2019 (COVID-19), it was found that the CONUT score predicted in-hospital mortality.[12] In another study, malnutrition as assessed by the CONUT score was found to have a remarkable correlation with the incidence of bleeding and stroke in individuals with AF aged 80 years and older.[13]

In the present study, our primary objective was to investigate the effect of the CONUT score on clinical outcomes in patients with AF aged 65 years and older. Our secondary objective was to evaluate variations in anticoagulant selection.

Medical history, demographic data, medications, laboratory and echocardiographic results of each patient were collected retrospectively from the hospital electronic clinical information system. The patients' CHADS-VASC and HAS-BLED scores were calculated. All patients were using anticoagulant medication. In patients receiving vitamin K antagonists (VKAs), time in therapeutic range (TTR) was defined as the time during which the patientsʼ international normalized ratio (INR) value was between 2 and 3. The TTR was calculated according to the Rosendaal method.[14] Patients with TTR >65% were considered to be receiving appropriate doses of warfarin. Patients with TTR <65% were excluded from the study. In patients receiving direct oral anticoagulants (DOACs), dose adjustment was adjusted according to the guideline recommendation.[15]

Evaluation of nutritional status
In our study, we used the CONUT score to assess nutritional status.[8] The CONUT score is calculated from serum albumin, total cholesterol and lymphocyte count (Table 1). According to the CONUT score, patients are categorized into four groups: normal (0-1), mild (2-4), moderate (5-8) and severe (9-12). In our study, patients were divided into two categories: normal-mild (0-4) and moderate-severe (≥5).

Table 1 CONUT scoring system

Follow-up
The primary outcome measures were ischemic stroke, major bleeding, and all-cause mortality. Ischemic strokes were characterized as clinical situations in which there was a sudden onset of neurological deficits that lasted at least 24 h, and this diagnosis was confirmed by computed tomography or magnetic resonance imaging. Major bleeding was determined according to the definition of the International Society on Thrombosis and Hemostasis (ISTH).[16] The records were reviewed over a period of at least two years from the first admission to the hospital for AF.

Statistical analysis
Statistical analysis was performed using the IBM SPSS version 25.0 software (IBM Corp., Armonk, NY, USA). Continuous data were expressed in mean ± standard deviation (SD) or median and interquartile range (IQR), while categorical data were expressed in number and frequency. The Kolmogorov-Smirnov test was utilized to assess the normality of the distribution for continuous variables. The Student t-test was applied for normally distributed variables, while the Mann-Whitney U test was employed for variables that did not follow a normal distribution. Categorical variables were compared using the chi-square test. Receiver operating characteristic (ROC) analysis was used to test the capacity of the CONUT score to predict mortality and major bleeding, as well as to determine a cut-off value based on the sum of the highest sensitivity and specificity. A p value of <0.05 was considered statistically significant.

Table 2 Baseline demographic characteristics of patients

Figure 1. Study flowchart.
CONUT: Controlling nutritional status.

The CONUT score was also evaluated in the DOAC and warfarin subgroups. Accordingly, major bleeding and mortality were significantly higher in patients with CONUT ≥5 in the warfarin subgroup, but no significant difference was found in the DOAC group (warfarin p=0.009, DOAC p=0.337 and warfarin p=0.046, DOAC p=0.171, respectively). In addition, there was no significant difference in terms of ischemic CVD/TIA in both subgroups according to the CONUT classification (warfarin p=0.223, DOAC p=0.760, respectively) (Figure 2).

Figure 2. Evaluation of CONUT score in DOAC and warfarin subgroups.
CONUT: Controlling nutritional status; DOAC: Direct oral anticoagulants.

Based on the ROC analysis, a cut-off value of 3.5 of the CONUT score predicted mortality with 72% sensitivity and 75% specificity (area under the curve [AUC]: 0.781, 95% confidence interval [CI]: 0.729-0.832, p<0.001) (Figure 3a). Similarly, in the ROC analysis, using this cut-off value, the CONUT score predicted major bleeding with 72% sensitivity and 71% specificity (AUC: 0.733, 95% CI: 0.635-0.831, p=0.001) (Figure 3b).

Figure 3. (a) ROC curve analysis of CONUT score on mortality in atrial fibrillation patients. (b) ROC curve analysis of CONUT score on major bleeding in atrial fibrillation patients.
ROC: Receiver operating characteristic; CONUT: Controlling nutritional status.

Elderly individuals, particularly those with cardiovascular disease, often suffer from malnutrition. Based on previous research, it has been found that approximately 60 to 90% of malnourished elderly people are below a healthy weight.[17] Around 60 to 70% of elderly people who are considered frail are malnourished.[18] Malnutrition is not only a consequence of chronic diseases, but can also contribute to the progression of these diseases. Previous studies have demonstrated a link between malnutrition and unfavorable outcomes in patients with coronary artery disease or heart failure.[19,20] However, there are few studies investigating both the incidence and predictive significance of malnutrition in patients with AF.[21,22]

The BMI is a commonly used measure for evaluating nutritional status. However, its use is limited, particularly in patients with AF. This is because 21 to 68% of patients with AF have also heart failure.[23] In individuals with heart failure, the retention of sodium and water in the body can lead to weight gain, which can affect the accuracy of BMI as a measure. In addition, BMI is unable to differentiate between muscle, fat and bone mass, and individuals with similar BMI values may have different metabolic profiles. The CONUT score is determined by measuring serum albumin, total cholesterol, and lymphocyte count. It serves as a comprehensive score that reflects the patient's frailty.

In our study, patients with a CONUT score of ≥5 were found to have a higher rate of major bleeding and mortality in the patient group receiving warfarin. However, no significant difference was observed between the groups in patients using DOAC. Polypharmacy often increases with age, as the prevalence of multiple health conditions or comorbidities increases. This situation increases the interaction of warfarin with other medications and, thus, it necessitates more frequent INR monitoring. Reduced muscle strength due to malnutrition limits physical activity and reduces hospital admissions.[24] This prevents regular follow-up and is one reason for the increase in the rate of major bleeding. Albumin level, one of the parameters in the CONUT score, is an important indicator reflecting nutritional status in clinical practice.[25] In addition, albumin levels also affect the efficacy of warfarin anticoagulation. Warfarin is completely absorbed after oral administration and subsequently binds to albumin in plasma to a high degree. The portion that remains unbound to albumin, about 1 to 10%, suppresses the synthesis of vitamin K-dependent coagulation factors in the hepatocytes, which leads to an anticoagulant effect. Previous studies have indicated increased anticoagulation and a higher risk of bleeding in individuals with low serum albumin levels receiving warfarin therapy.[26,27] These factors may explain the higher incidence of major bleeding and higher mortality in malnourished elderly AF patients taking warfarin in our study.

The assessment of malnutrition in patients with AF and the implementation of early interventions, particularly in patients with moderate to severe malnutrition, could have a significant impact on patient outcomes. Some studies have shown that the use of oral nutritional supplements and nutritional counseling can improve clinical outcomes in individuals with malnutrition.[28,29] The identification of malnutrition as an isolated risk factor for morbidity and mortality in elderly individuals with AF is important as malnutrition is a risk factor that can potentially be addressed and modified. Therefore, it is of great importance to develop a multidisciplinary team approach to reduce the negative effects of malnutrition in elderly patients with AF treated with anticoagulants. The recommendations of clinical nutritionists can play a crucial role in the development of a monitoring strategy. Incorporating oral nutritional supplementation can prove to be a valuable resource in preventing weight loss, enhancing nutritional health, and lowering complications in elderly AF patients suffering from malnutrition.

Nonetheless, there are some limitations to this study. The study was carried out in a retrospective manner at two centers, and the study sample size was relatively limited. In addition, we evaluated nutritional status exclusively at the moment of the initial hospital admission and did not explore any fluctuations or changes in nutritional status over the course of time. Therefore, it is not definitively established whether patients who had malnutrition at the beginning can maintain the same nutritional status, when they undergo clinical events. Finally, we only used the CONUT score to determine nutritional status. Therefore, we were not able to make a comparison with other nutritional scores with proven prognostic value.

In conclusion, the CONUT score is a critical measure used to evaluate the nutritional status of patients with AF. In our study, major bleeding and mortality rates increased, particularly in AF patients aged 65 and over who used anticoagulants and experienced moderate to severe malnutrition. We believe that the use of DOACs would be more appropriate in this patient group.

Ethics Committee Approval: The study protocol was approved by the Mardin Artuklu University Ethics Committee (date: 06.11.2023, no: 2023/11-20). The study was conducted in accordance with the principles of the Declaration of Helsinki.

Patient Consent for Publication: A written informed consent was obtained from each patient.

Data Sharing Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.

Author Contributions: Idea/concept, design, control/ supervision, data collection and/or processing, analysis and/or interpretation, literature review, writing the article, critical review, references and fundings, materials: R.K.; Design, control/supervision, data collection and/or processing, literature review, critical review, references and fundings, materials: A.F.K.

Conflict of Interest: The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding: The authors received no financial support for the research and/or authorship of this article.

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