Impact of initial high sensitivity C-reactive protein on outcomes in nonvalvular atrial fibrillation: an observational study

Abstract

Aim: The index study aimed to investigate the clinical impact of initial high-sensitivity C-reactive protein (hs-CRP) on outcomes in nonvalvular atrial fibrillation (AF). Methods: Single-center, prospective, observational study recruiting all recently diagnosed treatment-naive AF patients. Hs-CRP was measured at baseline and patients were followed for 24 months. Results: A total of 126 patients with a mean age of 66.2 (±12.0) years were enrolled. The composite outcome of major adverse cardiac or cerebrovascular events (MACCE) occurred in 19 (17.7%) at 24 months. Raised initial hs-CRP emerged as an independent predictor of MACCE on regression analysis (OR: 1.569, 95% CI: 1.289–1.912; p < 0.001). Conclusion: Raised hs-CRP was an independent predictor of MACCE at 24 months. It allows for early identification of high-risk patients.

Plain language summary

Atrial fibrillation (AF) is the most common cause of irregular heartbeat in adults. It has a significant association with clot formation in the heart and acute vessel closure throughout the vascular system particularly of the brain causing stroke. Stroke has a significant impact on quality of life and also is associated with an increased likelihood of death. Inflammation has been linked to the development and progression of AF. In this study, we evaluated the role of a simple inflammatory blood parameter – high sensitivity C-reactive protein (hs-CRP) with adverse outcomes in 126 AF patients at our center over a period of 2 years. We concluded that hs-CRP was an independent predictor of worse cardiovascular outcomes in AF patients and can help in the earlier identification of high-risk patients, for whom appropriate measures can be taken to prevent adverse events.

Plain language summary

Article highlights.

• Inflammation is a key pathogenic process in the initiation and progression of atrial fibrillation (AF).

• hs-CRP is one of the most commonly used biomarkers used in clinical practice and has shown substantial value in atherosclerotic vascular disease.

• We conducted the index study to better understand the clinical impact of initial hs-CRP on outcomes in nonvalvular AF.

• Single-center, prospective, observational study recruiting all recently diagnosed (≤3 months) treatment-naive, persistent nonvalvular AF patients.

• hs-CRP levels were obtained for all at the initial diagnoses.

• Follow-up period was 24 months.

• A total of 126 patients were recruited.

• The mean hs-CRP was 3.71 (±3.73) mg/l.

• Composite outcome of major adverse cardiac or cerebrovascular events (MACCE) occurred in 19 (17.7%) at 24 months.

• On univariate analysis, a higher CHA₂DS₂-VASc score, the presence of anemia, and raised hs-CRP all were significantly associated with the occurrence of MACCE.

• Raised initial hs-CRP emerged as an independent predictor of MACCE on regression analysis.

• hs-CRP value of >4.60 mg/l on presentation had a sensitivity of 84.2% and specificity of 88.6% for predicting the occurrence of a future MACCE at 24 months.

• hs-CRP was also associated with increased stroke, cardiovascular death, bleeding events, and overall mortality at 24 months.

• Incorporating hs-CRP allows early identification of high-risk patients and enables the timely institution of appropriate measures.

1. Background

Atrial fibrillation (AF) remains the most common sustained cardiac arrhythmia with increasing prevalence worldwide. It confers a substantially increased risk for stroke, heart failure, myocardial infarction, dementia, and death [1–5]. Inflammation is a key pathogenic process in the initiation and progression of AF. Further, inflammation contributes to increased systemic thrombogenicity irrespective of AF [6,7]. hs-CRP, a plasma protein belonging to the pentraxins family, is an acute phase reactant and remains one of the most commonly used biomarkers in clinical practice. It reliably indicates the presence and magnitude of systemic inflammation [8]. Increased hs-CRP correlates with increased major adverse cardiac or cerebrovascular events (MACCE) across the spectrum of cardiovascular diseases [9]. However, its clinical utility in AF has largely been subdued due to conflicting evidence from recent research. We conducted the index study to better understand the clinical impact of initial hs-CRP on outcomes in nonvalvular AF.

2. Methods

2.1. Study protocol

This was a single-center, prospective, observational study carried out in a tertiary care center in northern India. All recently diagnosed (≤3 months), treatment-naive, persistent nonvalvular AF patients presenting to the outpatient department (OPD) and fulfilling the selection criteria from July 2018 to June 2019 were enrolled. All patients underwent detailed history taking, physical examination, 12-lead electrocardiogram, echocardiogram, and basic laboratory investigations including hs-CRP at the time of recruitment. Invasive or computed tomography angiography was performed whenever there was suspicion of underlying coronary artery disease (CAD). The patients were followed up at 3–6 monthly intervals in OPD. Those unable to visit OPD during the specified time interval were contacted telephonically and asked about their well-being using a health questionnaire to determine the occurrence of various study end points.

The primary objective of the study was to determine the impact of initial hs-CRP on outcomes in nonvalvular AF. The study was not intended to investigate a correlation between AF and hs-CRP. All patients were followed for a minimum of 24 months post-recruitment to determine the occurrence of MACCE. The relationship of hs-CRP with various outcome parameters was analyzed at the end of the study period.

2.2. Hs-CRP measurement

Hs-CRP measurement was obtained from a venous sample (3 ml) drawn from an antecubital vein using a quantitative CRP solid-phase ultrasensitive immunoassay (CRP Ultra EIA; Xema Co. Ltd, Moscow, Russia). According to the manufacturer's instructions, the quantitative value of hs-CRP was determined using a calibration curve. This hs-CRP assay using enzyme-linked immune sorbent assay, has the ability to measure hs-CRP in the range of 0.007 mg/l allowing for estimation of minute variation in blood levels among participants.

2.3. Selection criteria

2.3.1. Inclusion criteria

• ▪Recently diagnosed (≤3 months) nonvalvular AF
• ▪Anticoagulation naive patients
• ▪Persistent AF
• ▪Willing to participate in the study

2.3.2. Exclusion criteria

• ▪Valvular AF
• ▪Prior anticoagulation use
• ▪Active infection
• ▪Underlying connective tissue disorder or malignancy
• ▪Recent acute coronary syndrome
• ▪Not willing to participate in the study

The rationale for selecting anticoagulant-naive patients was to limit confounders influencing inflammation among AF patients. Initiation of oral anticoagulation in AF patients often leads to reduced inflammation secondary to the underregulation of inflammatory cytokines. Recent studies have demonstrated the anti-inflammatory effect of newer oral anticoagulants as one of the pleiotropic effects when used in AF patients [10,11].

2.4. Statistical analysis & ethical justification

Statistical analysis was performed with Statistical Package for the Social Sciences version 26 (SPSS Inc, IL, USA). Variables are presented as mean ± SD. Continuous variables with normal distribution were compared using independent samples Student's t-test and those with non-normal distribution using a Mann-Whitney U test. Comparison between categorical variables was done using chi-square or Fisher exact test. Variables significantly associated with MACCE on univariate analysis were included in a multivariable regression analysis to identify independent predictors of outcomes. A two-sided p-value < 0.05 was considered to be significant for all variables. The study protocol conformed to the ethical guidelines of the recent declaration of Helsinki updated in October 2013. Written informed consent was obtained directly from all study participants prior to enrolment in the study. All patients were managed according to the recent guidelines for the management of AF [12]. The protocol of this study was reviewed and cleared by the ethical committee of the Postgraduate Institute of Medical Education and Research, Chandigarh, India; no INT/IEC/2019/000758 (ref no: NK/5215/DM/683).

3. Results

3.1. Baseline characteristics

A total of 126 patients were recruited over a 12-month period and underwent initial clinical assessment, echocardiography, and hs-CRP measurement. Table 1 shows the baseline characteristics of the study group. The mean age of the study population was 66.2 (±12.0) years. Among the comorbidities, hypertension was the most common comorbidity being present in 85 (67.5%) patients. Overall, the study population comprised a population having a high prevalence of cardiovascular comorbidities with a mean CHA₂DS₂VASc score of 3.0 (±1.2) and a mean HAS-BLED score (a simple and commonly used score at the bedside to assess the bleeding risk in AF patients [13]) of 1.9 (±1.3). Anemia (hemoglobin ≤ 12 gm/dl in females and ≤13 gm/dl in males) was present in 59 (46.8%) patients.

Table 1.

Baseline patient characteristics and outcomes.

Variable	Frequency (n = 126)
Mean age in years (±SD)	66.1 (±12.0)
Sex, n (%) (n = 108)
Female	50 (39.7%)
Male	76 (60.3%)
Mean BMI (kg/m2) (±SD)	24.6 (±3.4)
Co-morbidities, n (%) (n = 115)
Diabetes mellitus	36 (28.6%)
Hypertension	85 (67.5%)
Coronary artery disease†	33 (30.5%)
Dyslipidemia	29 (23.0%)
Chronic kidney disease	25 (19.8%)
Obesity (BMI ≥ 25 Kg/m2.)	55 (43.7%)
Smoking	25 (19.8%)
Alcohol intake (>2 drinks/day)	44 (34.9%)
CHA2DS2VASc score	3.1 (±1.2)
HAS-BLED score	1.9 (±1.2)
Echocardiographic parameters n (%) (n = 126)
Mean LVEF (%) (±SD)	45.6 (±14.3 %).
Laboratory parameters, n (%) (n = 126)
Anemia	59 (46.8%)
Hemoglobin (gm/dl ± SD)	12.6 (±1.8)
Mean creatinine (mg/dl ± SD)	1.3 (±0.9)
Mean albumin (gm/dl ± SD)	3.9 (±0.4)
Hs-CRP (mg/l ± SD)	3.71 (±3.73)
Anticoagulation data, n (%) (n = 126)
CHA2DS2-VASc ≤ 1	14 (10.1%)
CHA2DS2-VASc ≥2	112 (89.9%)
Total patients initiated on oral anticoagulation at presentation, n (%) (n = 83)
Total NOACs prescription   – Dabigatran   – Rivaroxaban   – Apixaban	58 (69.8%) 40 (48.1%) 12 (14.4%) 6 (7.2%)
Vitamin K antagonists	25 (30.1%)
Outcomes at 24 months, follow-up (n) available for 107 patients
Overall MACCE	19 (17.7%)
Stroke	9 (8.4%)
Myocardial infarction	1 (0.9%)
Heart failure	5 (4.6%)
Cardiovascular death	4 (3.7%)
Overall death	6 (5.6%)
Major bleeding complications	9 (8.4%)

All values are presented as the n (%). Continuous variables were presented as mean ± SD.

^†Available data for 108 patients.

BMI: Body mass index; LVEF: Left ventricular ejection fraction; MACCE: Major adverse cardiac or cerebrovascular event; NOAC: Newer oral anticoagulant.

Invasive angiography, computed tomography angiography, or noninvasive stress testing to rule out underlying CAD was performed in 108 (85.7%) patients. Out of these 33 (30.5%) patients had evidence of underlying CAD and were managed, according to the current standard of care guidelines. The mean hs-CRP of the study population was 3.71 (±3.73) mg/l.

3.2. Outcomes & determinants of outcomes

Out of the 126 patients recruited, a 24-month follow-up was available for 107 (84.9%) patients. Overall, the composite outcome of MACCE occurred in 19 (17.7%) at the end of 24 months (Table 1). Individually, stroke occurred in 9 (8.4%), myocardial infarction in 1 (0.9%), heart failure hospitalization in 5 (4.6%) and cardiovascular death in another 4 (3.7%) patients. The overall mortality of the study group at the end of 24 months was 5.6%. Major bleeding (fatal bleeding, any intracranial bleed, bleed that causes >2 gm/dl hemoglobin fall or needing 2 or more packed cell transfusion) occurred in 9 (8.4%) patients.

Various demographic, echocardiographic, and laboratory parameters were evaluated for their relationship with outcome variables. On univariate analysis (Table 2), a higher CHA₂DS₂-VASc score [3.8 ± 0.7 vs 2.9 ± 1.3; p = 0.002], presence of anemia [15 (78.9%) vs 37 (42.0%); p = 0.005] and a raised initial hs-CRP [9.0 ± 4.5 vs 2.5 ± 2.4; p = 0.001], all were significantly associated with the occurrence of MACCE at 24 months. The type of oral anticoagulation used had no bearing on the occurrence of MACCE (p = 0.42) at 24 months.

Table 2.

Demographic, echocardiographic, and laboratory parameters affecting major adverse cardiac or cerebrovascular event.

Variable	No MACCE (n = 88)	MACCE (n = 19)	p-value
Age, years, mean (±SD)	65.4 (±12.6)	69.8 (±7.4)	0.21
BMI, (kg/m2) mean ± (SD)	24.7 ± 3.6	24.6 ± 3.6	0.88
Sex, n (%)
Male	55 (62.5%)	10 (52.6%)	0.42
Female	33 (37.5%)	9 (47.4%)
Diabetes, n (%)	26 (29.5%)	6 (31.6%)	0.86
Hypertension, n (%)	59 (67.0%)	13 (68.4%)	0.90
CAD, n (%)	23 (26.1%)	8 (42.1%)	0.13
Dyslipidemia, n (%)	23 (26.1%)	3 (15.8%)	0.34
Smoking, n (%)	18 (20.5%)	4 (21.1%)	0.95
Alcohol intake, n (%)	33 (37.5%)	14 (73.7%)	0.35
CHA2DS2-VASc score, mean ± (SD)	2.9 ± 1.3	3.8 ± 0.7	0.002 †
HAS-BLED score, mean ± (SD)	1.8 ± 1.3	2.1 ± 0.7	0.20
Anemia, n (%)	37 (42.0%)	15 (78.9%)	0.005 †
Echocardiographic parameters
LVEF, %, mean ± (SD)	46.7 ± 13.8	40.5 ± 15.6	0.10
Laboratory parameters
Mean hemoglobin (gm/dl ± SD)	12.7 ± 1.8	11.6 ± 1.2	0.007 †
Mean TLC count (1000/dl SD)	819 ± 2.2	8.8 ± 2.2	0.18
Mean creatinine mg/dl ± SD)	1.3 ± 1.0	1.3 ± 0.5	0.15
Mean albumin gm/dl ± SD)	3.9 ± 0.4	4 ± 0.4	0.62
Hs-CRP (mg/l ± SD)	2.52 ± 2.36	9.04 ± 4.52	0.001 †

^†Bold values to highlight the statistically significant variables p <0.05.

BMI: Body mass index; CAD: Coronary artery disease; LVEF: Left ventricular ejection fraction; MACCE: Major adverse cardiac or cerebrovascular event; TLC: Total leukocyte count; VKA: Vitamin K antagonist.

These parameters were further evaluated using binary logistic regression to determine the independent predictors of MACCE at 24 months (Table 3). Anemia and raised initial hs-CRP emerged as the only independent predictors of MACCE on regression analysis (OR: 7.607, 95% CI: 1.324–43.714; p = 0.02 and OR: 1.569, 95% CI: 1.289–1.912; p < 0.001). On the receiver operating characteristic curve, an initial hs-CRP value of >4.60 mg/l on presentation had a sensitivity of 84.2% and specificity of 88.6% (AUC, 0.898; 95% CI, 0.814–0.981; p = 0.001) for predicting the occurrence of a future MACCE at 24 months (Figure 1).

Table 3.

Binary logistic regression analysis.

Risk factors	Multivariable analysis
	OR	CI (95%)	p-value
CHA2DS2-VASc score	1.363	0.667–2.783	0.39
Anemia	7.607	1.324–43.714	0.02 †
Hs-CRP	1.569	1.289–1.912	<0.001 †

^†Bold values to highlight the statistically significant variables p <0.05.

OR: Odds ratio; CI: Confidence interval.

Figure 1.

Receiver operating characteristic curve showing the excellent accuracy of initial hs-CRP in predicting major adverse cardiac or cerebrovascular events at 24 months. An initial hs-CRP value of >4.60 mg/l on presentation had a sensitivity of 84.2% and specificity of 88.6% (AUC, 0.898; 95% CI, 0.814–0.981; p = 0.001) for predicting the occurrence of a future MACCE at 24 months.

AUC: Area under curve; CI: Confidence interval; MACCE: Major adverse cardiac or cerebrovascular event; ROC: Receiver operating curve.

3.3. Comparison of clinical profile of patients with elevated & normal hs-CRP

Comparison of various demographic, laboratory, and outcome parameters among the groups with elevated hs-CRP (>3 mg/l) and those with hs-CRP within the normal limit (≤3 mg/l) was performed. Patients with raised hypertension and underlying CAD were more prevalent in the group with raised hs-CRP (p = 0.04 for both, Table 4) whereas alcohol consumption was less frequently seen in the group with raised hs-CRP (p = 0.001). Patients with raised hs-CRP had higher cardiometabolic comorbidities as reflected by increased mean CHA₂DS₂-VASc and HAS-BLED scores compared with those with normal hs-CRP levels. In terms of outcomes, patients with raised hs-CRP levels had increased overall MACCE, stroke, cardiovascular death, and overall mortality at 24 months (Table 4 & Figure 2).

Table 4.

Differences in demographic, echocardiographic, and laboratory parameters among those with normal (≤3 mg/l) and those with raised initial hs-CRP (>3 mg/l).

Variable	hs-CRP (≤3 mg/l) (n = 62)	hs-CRP (>3 mg/l) (n = 45)	p-value
Age, years, mean (±SD)	64.5.6 (±13.2)	68.4 (±9.8)	0.04 †
BMI, (kg/m2) mean ± (SD)	24.5 ± 3.5	24.8 ± 3.3	0.35
Sex, n (%)
Male	43 (59.7%)	33 (61.1%)	0.87
Female	29 (40.3%)	21 (38.9%)
Diabetes, n (%)	20 (27.8%)	16 (29.6%)	0.82
Hypertension, n (%)	43 (59.7%)	42 (77.8%)	0.04 †
CAD, n (%)	14 (19.4%)	19 (35.2%)	0.04 †
Smoking, n (%)	12 (16.7%)	13 (24.1%)	0.36
Alcohol intake, n (%)	34 (47.2%)	10 (18.5%)	0.001 †
CHA2DS2-VASc score, mean ± (SD)	2.7 ± 1.3	3.4 ± 1.0	0.001 †
HAS-BLED score, mean ± (SD)	1.6 ± 1.1	2.2 ± 1.3	0.03 †
LVEF, %, mean ± (SD)	45.7 ± 14.2	45.6 ± 14.5	0.96
Laboratory parameters
Mean hemoglobin (gm/dl ± SD)	12.7 ± 1.9	12.4 ± 1.6	0.27
Mean creatinine mg/dl ± SD)	1.3 ± 1.1	1.2 ± 0.5	0.22
Mean albumin gm/dl ± SD)	3.9 ± 0.4	3.9 ± 0.4	0.62
Outcome parameters
MACCE events, n (%)	3 (4.8%)	16 (35.6%)	0.001 †
CVA, n (%)	2 (3.2%)	7 (15.6%)	0.03 †
MI, n (%)	0	1 (2.2%)	0.23
Heart failure, n (%)	1 (1.6%)	4 (8.9%)	0.15
CV death, n (%)	0	4 (8.9%)	0.03 †
Overall mortality, n (%)	1 (1.6%)	5 (11.1%)	0.03 †
Bleeding events, n (%)	1 (1.6%)	8 (17.8%)	0.004 †

^†Bold values to highlight the statistically significant variables p <0.05.

BMI: Body mass index; CAD: Coronary artery disease; CVA: Cerebrovascular accident; CV: Cardiovascular death; LVEF: Left ventricular ejection fraction; MACCE: Major adverse cardiac or cerebrovascular event; MI: Myocardial infarction.

Figure 2.

Survival analysis. The Kaplan-Meier curve shows the increased MACCE at 24 months in the group with raised hs-CRP (>3 mg/l) compared with those with normal hs-CRP (≤3 mg/l) (4.8 vs 36.6%; p = 0.001).

CV: Cardiovascular death; MACCE: Major adverse cardiac or cerebrovascular event.

4. Discussion

hs-CRP remains one of the most widely studied biomarkers among the systemic markers of inflammation. Raised hs-CRP levels have been shown to correlate with worse clinical outcomes even in otherwise healthy individuals without underlying cardiovascular disease [14]. Further, in regards to atherosclerotic vascular disease, recent research indicates that hs-CRP correlates well with not only the presence and extent of CAD but also with overall morbidity and mortality [8,9,15]. Despite the strong evidence supporting the significant impact of hs-CRP in atherosclerotic vascular disease, its role in the management and prognosis of patients with AF is far from conclusive.

Accumulating evidence suggests that inflammation is a key pathophysiological mechanism in the initiation and perpetuation of AF [6]. The earliest evidence supporting this theory came from the observation of a high incidence of AF (30 to 40%) post-cardiac surgeries which usually resolved after a few weeks. There is exaggerated activation of proinflammatory cytokines and the complement system post-cardiac surgery leading to an intense inflammatory response [16]. Among the inflammatory cytokines, hs-CRP is the most commonly implicated which starts increasing immediately postoperatively and it usually achieves a peak serum concentration 48 to 72 h after cardiac surgery. This in fact coincides with the time frame when the occurrence of atrial arrhythmias is highest post cardiac surgery. Even in nonoperative AF cases, histological evidence from atrial biopsies of lone AF patients shows the increased predominance of inflammatory cells, atrial myocyte necrosis, myosin isoform switching, and fibrosis [17].

In line with the theory of inflammation playing a key role in AF, multiple studies have emerged that support raised hs-CRP among AF patients compared with age-matched controls. A study by Chung et al. showed that hs-CRP was >twofold higher in AF patients compared with age and comorbidity-matched controls with no AF. Further, the magnitude of hs-CRP elevation also correlates with the burden and type of AF [18]. Consequently, persistent and permanent AF patients have considerably higher levels of hs-CRP compared with those with paroxysmal AF. AF recurrence postcardioversion is another important parameter that is strongly related to pre-cardioversion hs-CRP levels. In a meta-analysis by Hung et al., baseline hs-CRP had a high positive predictive value for predicting the recurrence of AF postcardioversion [19]. In the recent, large prospective study by Meyre et al. pre-ablation hs-CRP >3 mg/l was independently associated with the recurrence of AF in the subsequent 12 months post-ablation [20].

All these data point toward the clinical relevance of the measurement of hs-CRP in AF patients. However, despite the initial results, hs-CRP has not uniformly been accepted as a potential tool in the evaluation and management of AF, especially in regard to long-term thromboembolic complications and MACCE. This is largely attributable to conflicting evidence from studies that have not shown hs-CRP to be a reliable indicator of thromboembolic risk in AF patients. The largest of them was the REGARDS study by Dawood et al. in which hs-CRP >3 mg/l predicted the occurrence of stroke in the general population but not in those suffering from AF [21]. Hence, the efficacy and utility of hs-CRP as a marker of thromboembolic risk in AF patients remained a matter of debate. For this particular reason, the index study sought to have more data as to the implications of initial hs-CRP for predicting MACCE events in the intermediate term. Our study goes far in supporting the measurement of hs-CRP during the initial evaluation of AF patients for early risk stratification and institution of aggressive disease-modifying therapies in the high-risk group with raised hs-CRP. In our study population, hs-CRP >4.60 mg/l reliably predicted MACCE at 24 months. Our findings are supported by some of the recent research that supports the incorporation of inflammatory biomarkers into risk stratification algorithms for personalized patient care. In the study by Wu et al., incorporating hs-CRP into the clinical variable improved the diagnostic accuracy for predicting stroke using machine learning in the Chinese population [22]. In another study by Yin et al., worse left atrial function and enhanced prothrombotic response were observed in patients with a raised hs-CRP undergoing ablation compared with those with a normal hs-CRP [23]. The same was argued in a recent review by Galenko et al. wherein the incorporation of inflammatory markers like hs-CRP into the conventional CHA₂DS₂-VASc score improved predictive utility and allowed for additional risk prognostication among AF patients [24]. Going further, Duan et al. showed that a high hs-CRP >3 mg/l was independently associated with early neurological deterioration following stroke compared with those with low <1 mg/l or average hs-CRP 1–3 mg/l [25].

In summary, results from our study support the incorporation of hs-CRP into the management armamentarium for AF. It allows early identification of high-risk individuals and enables the institution of appropriate measures to prevent MACCE. We believe it would only pave the way for further larger studies to generate more data and validate our findings. Inflammation plays a key pathogenic role in all stages of AF right from its initiation to its progression and adverse effects on the cardiovascular system. Recent studies have indicated that CRP may not only be a marker of inflammation in patients with AF but may also play an active pathophysiological role. Further elevated CRP often is closely elevated with worsening of endothelial function which further aggravates AF culminating in its progression. However, current data on this topic is insufficient to conclude whether CRP has an actual role in pathogenesis or is simply the end product because of heightened inflammation. This necessitates clinical and experimental studies which will shed more light on this relevant problem. Still, we believe prior and our research points to the fact that analysis of a simple inflammatory marker like CRP opens new doors toward pharmacological interventions that will modulate inflammation among AF patients.

While there are certain merits of our study, we must also accept the limitations of our study. The major limitations of our study included a relatively small number of patients for a common disease which was largely due to the stringent selection criteria (only newly diagnosed anticoagulation naive AF patients). Secondly, this was only a single-center observational study and hence the results may not be generalizable to all AF patients. Thirdly, not all patients underwent invasive or noninvasive imaging to rule out CAD which might have confounded the results as it can independently lead to elevations in hs-CRP. Another limitation was the fact we did not take into account statin usage among the study participants. Statin have the ability to lower hs-CRP levels and can also influence the occurrence of MACCE independently. Accounting for statin dosage and intensity would have allowed us to have a more comprehensive real-world picture. Lastly, we measured hs-CRP only at the onset of the study and recruitment. It would have been more informative had we looked into the serial hs-CRP values.

5. Conclusion

Inflammation is a key pathophysiological mechanism in the initiation and perpetuation of AF. Our study supports the emerging evidence surrounding the clinical utility of hs-CRP, the most commonly used inflammatory biomarker in AF. In our study, we showed that a higher initial hs-CRP was an independent predictor of MACCE at 24 months. Initial hs-CRP value of >4.60 mg/l had excellent accuracy for predicting the occurrence of a future MACCE at 24 months. These results support the incorporation of hs-CRP into the management armamentarium for AF. It allows early identification of high-risk individuals and enables the institution of appropriate measures.

Author contributions

Patient management: A Batta, P Panda, YP Sharma; writing the manuscript: A Batta, J Hatwal; Reviewing: YP Sharma, A Batta, B Mohan; key insights: A Batta, P Panda; Revision- A Batta, YP Sharma, Approval and supervision: A Batta, GS Wander, B Mohan, YP Sharma. All authors have read and approved the manuscript.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The study protocol conformed to the ethical guidelines of the recent declaration of Helsinki updated in October 2013. All patients were managed according to the recent guidelines for the management of AF. All study participants enrolled in the study were aged 18 years or more. None of the participants had any significant mental/neurological limitations that would limit their comprehension of the study protocol. Accordingly, written informed consent was obtained directly from the participants for participation in this study and its subsequent publication. The protocol of this study was reviewed and cleared by the ethical committee of the Postgraduate Institute of Medical Education and Research, Chandigarh, India; no INT/IEC/2019/000758 (ref no: NK/5215/DM/683).

Data availability statement

All data and materials will be uploaded as per the needs of the editor/reviewer or the readers as per their request.