European Journal of Cardiovascular Medicine

Coronary artery disease (CAD) is one of the most common causes of mortality and morbidity across the globe. It’s the leading cause of demise in India, and the contribution to mortality is rising. Number of deaths because of CAD in the year 1985 doubled by 2015.¹ Conventional risk factors for CAD can be divided into non-modifiable and modifiable risk factors. The former includes age, gender and family history, while the latter includes diabetes mellitus (DM), smoking, dyslipidaemia, hypertension and obesity.  Recently, a number of newer cardio-vascular biomarkers have been identified, that are of great interest as more than 60.0% CAD in the Indians remains unexplained by the conventional risk factors.^{2 ,3} Recently, an attempt has been made to incorporate these biomarkers into traditional scoring systems to add to their prognostic value, however, risk stratification of CAD remains far from perfect.⁴ The goal of risk stratification is not only to predict outcomes but also to guide management, triaging and more importantly urgency of treatment needed. This is even more relevant in a resource-constrained setting.⁵

Fibrinogen is a short half-life protein and an indicator of the state of coagulation and a biomarker of inflammation.⁶ It’s reported that the level of plasma fibrinogen in the patients having ACS was much higher than healthy controls and a higher level of plasma fibrinogen may be an independent predictor of the major adverse cardiac events during the short- term, and long-term follow-up.⁷ On the contrary, albumin is inversely related to the degree of the inflammatory response and it’s an important inhibitor of platelet activation and aggregation.⁸ Studies indicate that low albumin is associated with atherosclerotic cardio-vascular diseases (ASCVD), and is related to major adverse cardio-vascular events (MACE).⁹  Hypoalbuminemia has been identified as a risk factor for incident myocardial infarction (MI) in cases with CAD.¹⁰ Several studies reported the association between low serum albumin and the increased risk of cardio-vascular mortality and morbidity.¹¹ 

The Fibrinogen/Albumin Ratio (FAR) has performed better than individual fibrinogen and albumin level in determining the severity of the acute myocardial infarction (AMI) and predicting short-term prognosis of these patients.^{12, 13} A prospective cohort investigation

conducted in China revealed that CVD patients with high FAR levels and diabetes had a poorer 5-year prognosis.¹⁴

Therefore, both fibrinogen and albumin are important factors of systemic inflammatory and hemorheological alterations. The fibrinogen–albumin ratio (FAR), comprising both of these indicators, has been reported as a new inflammatory marker closely related to CAD progression and severity of CAD.¹³ However, the prognostic value of the FAR for patients with CAD among the Indian population is unclear. Purpose of this study is to explore the relationship between the FAR and angiographic severity of CAD and short-term prognosis in Indian patients with CAD who are undergoing coronary angiography and revascularization.

OBJECTIVE:  Primary objective of this study was to study association of FAR with angiographic severity of the coronary artery disease as measured by SYNTAX Score. Secondary objectives were to study association of FAR with Major adverse cardiovascular events (MACE) (composite of cardiovascular death, nonfatal myocardial infarction, target vessel revascularization, and stroke) at 6 months after angiography and periprocedural outcomes (including heart failure events, bleeding events, rehospitalization, slow flow/ no-reflow during PCI).

This was a single-centre, prospective, observational study conducted in the Department of

Cardiology at a tertiary care teaching institute in north India.  During the study period of 14 months, eligible patients of either gender who were undergoing coronary angiography for suspected CAD/ACS, were recruited into the study, if they consented for participation. Sample Size was calculated to be 191 for a power of 80 percent.

Adult patients (age >18 years) of either gender, who were clinically diagnosed as stable CAD or ACS (ST elevation MI, Non-ST elevation MI and unstable angina) and were admitted for undergoing coronary angiography or revascularization were   invited to participate in the study; provided they gave a written informed consent and were available for follow-up for at least 6 months.

Patients who had previously undergone percutaneous coronary intervention (PCI), or coronary artery bypass surgery (CABG) or had normal epicardial coronary arteries were excluded. Patients with CHF, myocarditis, cardiomyopathies, and pulmonary embolism were excluded. Patients having severe malnutrition, COPD, cancer, end stage liver, or renal failure, active systemic infection, hyperthyroidism, autoimmune disease, and active tuberculosis were also excluded. 

A detailed history, physical examination and routine investigations including CBC, renal function test, liver function test, lipid profile, serum albumin, fibrinogen, and ECG were done for all the patients. Samples were drawn at admission, before angiography. A 2-D echocardiogram for assessment of LV function was performed on each patient before the procedure.

Venous blood sample (2 ml) was drawn in plain and sodium citrate vacutainer in each for albumin and fibrinogen estimation respectively in the morning prior to coronary angiography.  Both samples were transported to the central biochemistry lab for quantitative analysis. For Serum albumin analysis, sample was centrifuged at 3500 rpm for 15 min, the serum was extracted and analysed by spectrophotometry with BCG (Bromo-Cresol Green) method on AU480, Beckman Coulter using the commercial kit from the same manufacturer. For Plasma fibrinogen analysis, the sample was centrifuged at 4000 rpm for 15-20 min, and plasma was separated and analysed by the clotting method of Clauss, using the commercial kit STA®, STA Compact®, and STA Satellite® for quantification of fibrinogen levels in plasma.

All the patients underwent clinically indicated invasive coronary angiography. SYNTAX SCORE (SS) was calculated using an online (https://syntaxscore2020.com) SYNTAX  SCORE calculator. Patients were categorized into mild CAD (SS < 23) or severe CAD (SS ≥23).    Based upon the angiographic findings further treatment strategy was decided by the treating physician and patient. The patients were followed-up by in-person hospital visits and evaluated for their clinical status including MACE and any new symptom(s) and concerning any major clinical event at 6 months. Patients who had cardiac symptoms underwent complete clinical, electrocardiographic, and laboratory evaluation. Data concerning the death of the patient was collected from the hospital registry and by a telephonic inquiry from relatives.

Statistical Analysis

All continuous values were summarized as Mean ± SD. Clinical and demographic characteristics of study groups were compared by means of the Student’s t-test for continuous variables. Categorical variables were presented in percentages, and compared using the χ2 statistics or Fisher exact test. A p-value < 0.05 was considered significant. All statistical tests were two-sided. Statistical analysis was performed using SPSS 23.0 version (IBM Corporation, USA).

Ethical Consideration: All procedures were done in accordance with the ethical standards of the institutional ethics committee and with the Helsinki Declaration of 1964 and later versions. Informed consent was obtained from all the patients participating in the study. It was an observational study with no intervention done to the patient.

Overall, 237 patients were recruited into the study. Mean age of the patients was 57 years ranging from 31 to 80 years. Mean BMI was 24.47 kg/m² (Table 1). Mean fibrinogen level was 397.97 mg/dl, the mean serum albumin level was 4.05 g/dl and the mean FAR was 101.07 mg/g. The mean value of FAR was taken as the reference value for the analysis below which it was considered as low FAR and above it was considered as high FAR. The mean CAG Syntax score was 22.02, suggesting an overall low complexity of coronary artery disease in study cohort.

Table 1: Distribution of studied patients based on baseline characteristics

Majority of study patients (81.4%) were male (Table 2). In terms of age, the highest percentage of patients (36.7%) were in the age group of 51-60 years followed by 22.4% in the age group of 41-50 years. Regarding the diagnosis, the majority of patients (41.4%) had stable coronary artery disease (CSA), while (35.4%) were diagnosed with ST-elevation myocardial infarction (STEMI). The remaining patients were diagnosed with non-ST elevation myocardial infarction (NSTEMI) and unstable angina.

Table 2: Distribution of studied patients based on the demographic profile

Admitting diagnosis was ACS in 58.6% and stable CAD in remaining 41.4 percent (Table 3). Regarding the duration of symptoms in stable CAD, most patients (49.4%) had symptoms for 1 month to 1 year, followed by 33.8% who had symptoms for less than 1 month and 16.8% who had symptoms for more than 1 year. Among patients with ACS, the majority of patients (40.5%) presented within for 2 to 7 days of symptom onset, followed by 32.9% who had symptoms onset 7 days to 1 month back and 17.3% who had symptoms more than 1 month back. Only 9.3% presented within 48 hours from onset of symptoms.

Table 3: Distribution of studied patients based on ACS vs CSA, duration of stable CAD and ACS

ACS patients who presented within 7 days of onset of ACS were found to have a statistically significant higher proportion of elevated FAR values as compared to those presenting beyond 7 days (Graph 1).

Graph 1: Distribution of studied patients based on the duration of ACS

No correlation was seen between the elevated FAR and angiographic severity of CAD as measured by Syntax score (Correlation between the FAR and CAG Syntax Score is shown in (Table 4).  Both high and low FAR groups were found to have similar distribution Syntax score of less than 23 or more than 23 (p=0.941).

Table 4: Correlation between FAR and CAG Syntax Score

No significant correlation was seen between the CAG Syntax score and serum albumin or fibrinogen levels (Table 5).

Table 5: Correlation of albumin and fibrinogen with Syntax Score

Very few secondary outcome events were reported during the follow-up period of 6 months. Three suspected CV deaths (unwitnessed) occurred, 2 were having high FAR values. Test for statistical significance could not be applied as the events were too less in number. All the other events including no-reflow/slow flow, major bleeding, heart failure, rehospitalization and MACE (excluding CV deaths) were not noticed in both the FAR groups.

Albumin is an essential protein in human plasma. It’s been proposed that the serum albumin concentration is inversely related to the inflammatory and the haemostatic processes. Fibrinogen, produced by the liver, serves as an indicator of the procoagulant state and plays a role in inflammatory responses at various levels.

Therefore, both fibrinogen and the albumin are main markers of systemic inflammatory, and hemorheological alterations. The fibrinogen–albumin ratio (FAR), comprising these two entities, has been reported as a new inflammatory marker closely related to CAD progression and severity of CAD.¹⁷

In the present study we noted that out of the 237 patients, the majority (81.4%) were male, while the remaining 18.6% were female. Swaminathan CR & Prasath PA ¹⁵ in their study of the correlation between the Clinical Profile and Angiographic Severity of CAD in ST Elevation Myocardial Infarction and Non-ST Elevation Myocardial Infarction Patients, reported that 82.3% of patients were males and 17.7% were females. This exhibits a striking male predominance in coronary artery disease in Indian patients, which was also observed in the present study.

Karahan O et al¹⁶ conducted a single-centre, observational study on relationship between FAR and the severity of CAD in STEMI cases and concluded that FAR was related significantly to SS in predicting the extent, and severity of CAD in STEMI cases.

Li M et al¹⁷ conducted a single-centre, observational study on the relation of FAR to the severity of CAD and the long-term prognosis in non-ST elevation ACS cases and concluded that FAR was independently associated with the severity of CAD, and prognosis, helping to enhance risk stratification in the NSTE-ACS cases undergoing PCI.

Celebi S et al¹⁸ conducted a single-centre, observational study on the association between FAR and CAD severity in stable CAD cases and concluded that the novel inflammatory index, FAR, was associated significantly with the severity of CAD among stable CAD cases.

Demir M et al¹⁹ conducted a single-center, observational study of FAR predicting burden of CAD among NSTEMI patients and concluded that in the moderate-high Syntax score (SS) group FAR value is considerably higher than those with the low SS group.

Present study had representation of both ACS and stable CAD, 58.6% had ACS and 41.4 % had stable CAD. Whereas, Karahan O et al¹⁶ studied only STEMI patients, Demir M et al¹⁹ and Li M et al¹⁷ studied NSTEMI-ACS patients, and Celebi S et al¹⁸ studied only stable CAD patients.

 In the present study, no statistically significant association was observed between FAR, and the Syntax Score(p>0.05). This is unlike the studies done by Karahan O et al¹⁶, Celebi S et al¹⁸ and Demir M et al¹⁹, which found that there was a significant correlation between FAR, and Syntax score (p< 0.05). Study by Li M et al¹⁷ also found that FAR was related significantly to Gensini Score in predicting CAD severity (p< 0.05).

Present study is the only study done among Indian CAD patients. The observed difference from previously published studies could have arisen due to racial variation, demographic variations and heterogenous study population (comprising of both stable CAD and ACS patients) recruited in the present study.

Li M et al¹⁷ conducted a single-centre, observational study on the relation of FAR to the severity of CAD and the long-term prognosis with non-ST elevation ACS cases. Their study showed that FAR was an independent predictor for the MACE at 30 days, 6 months, and 1 year after the DES implantation.

Present study did not find a correlation between FAR, and the short-term prognosis of CAD among the Indian population. Low event rates observed during the study duration in the present study as well as racial and demographic differences could have resulted in the lack of correlation between FAR and MACE in the present study.

Study Limitations:

 There are some significant limitations with present study, which we accept. They include it being a single-centre, observational study with relatively small sample size. Delayed presentation (> 48 hours) was seen among 90% of ACS patients. Follow-up period of 6 months may be relatively short.

Conclusion:       

In conclusion, FAR was not found to be associated with CAD severity among Indian patients with stable CAD and ACS in the present study. FAR was not found to be a predictor of short-term MACE in the study population.

1. Misra A, Nigam P, Hills AP, et al. Consensus physical activity guidelines for Asian Indians. Diabetes Technol Ther. 2012;14:83–98.
2. Reddy KS, Yusuf S. Emerging epidemic of cardiovascular disease in developing countries. Circulation. 1998;97:596–601.
3. Sekhri T, Kanwar RS, Wilfred R, et al. Prevalence of risk factors for coronary artery disease in an urban Indian population. BMJ Open 2014;4:e005346.
4. Klingenberg R, Aghlmandi S, Räber L, Gencer B, Nanchen D, Heg D, et al. Improved risk stratification of patients with acute coronary syndromes using a combination of hsTnT, NT-proBNP and hsCRP with the GRACE score. Eur Heart J Acute Cardiovasc Care. 2018;7:129-138.
5. Makkar K, Sharma YP, Batta A, Hatwal J, Panda PK. Role of fibrinogen, albumin and fibrinogen to albumin ratio in determining angiographic severity and outcomes in acute coronary syndrome. World J Cardiol.2023; 15(1): 13-22.
6. Tabakci MM, Gerin F, Sunbul M, et al. Relation of plasma fibrinogen level with the presence, severity, and complexity of coronary artery disease. Clin Appl Thromb/Hemost. 2017;23(6):638–44.
7. Shi Y, Wu Y, Bian C, et al. Predictive value of plasma fibrinogen levels in patients admitted for acute coronary syndrome. Texas Heart Inst J. 2010;37(2):178.
8. Gresele P, Deckmyn H, Huybrechts E, et al. Serum albumin enhances the impairment of platelet aggregation with thromboxane synthase inhibition by increasing the formation of prostaglandin D2. Biochem Pharmacol. 1984;33(13):2083–8.
9. Zhu L, Chen M, Lin X. Serum albumin level for prediction of all-cause mortality in acute coronary syndrome patients: a meta-analysis. Biosci Rep. 2020;40(1):BSR20190881.
10. Nelson JJ, Liao D, Sharrett A, Folsom AR, Chambless LE, Shahar E. Serum albumin level as a predictor of incident coronary heart disease. The atherosclerosis risk in communities (ARI) study. Am J Epidemiol. 2000;151:468-77
11. Oduncu V, Erkol A, Karabay CY, Kurt M, Akgün T, Bulut M. The prognostic value of serum albumin levels on admission in patients with acute ST-segment elevation myocardial infarction undergoing a primary percutaneous coronary intervention. Coron Artery Dis. 2013;24:88-94
12. Erdogan G, Arslan U, Yenercağ , Durmuş G, Tuğrul S, Şahin İ, et al. Relationship Between the Fibrinogen-to-Albumin Ratio and SYNTAX Score in Patients with Non-St-Elevation Myocardial Infarction. Rev Invest Clin. 2021;73(3):182-9
13. Zhao Y, Yang J, Ji Y, Wang S, Wang T, Wang F, et al. Usefulness of fibrinogen-to-albumin ratio to predict no-reflow and short-term prognosis in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Heart Vessels.2019;34:1600–1607.
14. Wang P, Yuan D, Zhang C, Zhu P, Jia S, Song Y, et al. High fibrinogen-to-albumin ratio with type 2 diabetes mellitus is associated with poor prognosis in patients undergoing percutaneous coronary intervention: 5-year findings from a large cohort. Cardiovasc Diabetol.2022;21:46. 
15. Swaminathan CR, Prasath PA. Correlation between the Clinical Profile and Angiographic Severity of Coronary Artery Disease in ST Elevation Myocardial Infarction and Non-ST Elevation Myocardial Infarction Patients. Ind J Car Dis Wom. 2021;6:145–154.
16. Karahan O, Acet H, Ertas F, Tezcan O, Caliskan A, Demir A. The relationship between fibrinogen to albumin ratio and severity of coronary artery disease in patients with STEMI. Am J Emerg Med. 2016; 34:1037-42.
17. Li M, Tang C, Luo E, Qin Y, Wang D, Yan G. Relation of Fibrinogen-to-Albumin Ratio to Severity of Coronary Artery Disease and Long-Term Prognosis in Patients with Non-ST Elevation Acute Coronary Syndrome. BioMed Research International. 2020; 1860268:1- 10.
18. Celebi S, Celebi OO, Berkalp B, Amasyali B. The association between the fibrinogen-to-albumin ratio and coronary artery disease severity in patients with stable coronary artery disease. Coron Artery Dis. 2020; 31:512-517.
19. Demir M, Ozbek M, Aktan A, Ertaş F. Fibrinogen to Albumin Ratio Predicts Burden of Coronary Artery Disease in Patients with NSTEMI. Dicle Tıp Dergisi / Dicle Med J. 2021;48 (4) : 688-695.