CHA2DS2‐VASc score predicts atrial fibrillation recurrence after cardioversion: Systematic review and individual patient pooled meta‐analysis

Background Despite progresses in the treatment of the thromboembolic risk related to atrial fibrillation (AF), the management of recurrences remains a challenge. Hypothesis To assess if congestive heart failure or left ventricular systolic dysfunction (CHA2DS2‐VASc) score is predictive of early arrhythmia recurrence after AF cardioversion. Methods Systematic review and individual patient pooled meta‐analysis following Preferred Reporting Items for Systematic reviews and Meta‐Analyses guidelines. Inclusion criteria: observational trials in patients with AF undergoing cardioversion, available data on recurrence of AF and available data on CHA2DS2‐VASc score. Clinical studies of interest were retrieved by PubMed, Cochrane Library, and Biomed Central. Seven authors were contacted for joining the patient level meta‐analysis, and three shared data regarding anthropometric measurements, risk factors, major comorbidities, and CHA2DS2‐VASc score. The primary outcome was the recurrence of AF after cardioversion in patients free from antiarrhythmic prophylaxis. Univariate and multivariate logistic regression was performed. Results Overall, we collect data of 2889 patients: 61% were male, 50% with hypertension, 12% with diabetes, and 23% with history of ischemic heart disease. The median CHA2DS2‐VASc score was 2.. At the multivariate analysis, chronic kidney disease (odds ratio [OR] 1.94; 95% confidence interval [CI] 1.12‐3.27; P = 0.01), peripheral artery disease (OR 1.65; 95% CI 1.23‐2.19; P < 0,0001), previous use of beta blockers (OR 1.5; 95% CI 1.19‐1.88; P < 0.0001), and CHA2DS2‐VASc score > 2 (OR 1.37; 95% CI 1.1‐1.68; P = 0.002) were independent predictors of early recurrence of AF. Conclusions CHA2DS2‐VASc score predicts early recurrence of AF in the first 30 days after electrical or pharmacological cardioversion. Protocol registration PROSPERO (CRD42017075107).

Despite progresses aimed to reduce the risk of stroke by new oral anticoagulants, 2-4 AF management remains somehow problematic because of the difficulty to predict recurrences that reduce quality of life, and increase hospital admissions. 1 Although trials comparing rhythm to rate control (with appropriate anticoagulation) resulted in neutral clinical outcomes, [5][6][7][8][9][10][11][12][13] a rhythm control strategy is currently considered the first option in patients with symptomatic AF, and in young patients with a first episode of the arrhythmia. 1 In paroxysmal AF, recurrent episodes are mainly due to factors triggering arrhythmias (triggers), whereas perpetuating factors (perpetrators) are the key elements in persistent and permanent AF. [14][15][16] Among perpetrators, different factors are considered as independent predictors for the reoccurrence of AF, such as advanced age, heart failure (HF), previous myocardial infarction (MI), hypertension, 17 , diabetes, obesity, 18 presence of valvular heart disease, 19 chronic obstructive pulmonary disease (COPD), 19,20 and cigarette smoking. 21 Those stressors induce a time-dependent maladaptive cascade of events with a progressive atrial structural and electrical remodeling leading to the development and maintenance of AF.
The CHA 2 DS 2 -VASc (congestive heart failure or left ventricular systolic dysfunction, hypertension; age ≥ 75 years; diabetes mellitus; prior stroke or transient ischemic attack (TIA) or thromboembolism; vascular disease; age 65-74 years; female sex), a score which predicts the risk of ischemic event, in patients with AF, 22 is currently considered the cornerstone for the management of anticoagulation therapy.
Because of the high consistency in the quantification of the thromboembolic risk, this score has been studied in different settings and not only in AF patients. Indeed, variables included in the CHA 2 DS 2 -VASc score are associated with the risk of stroke in patients without AF but affected by acute coronary syndrome. 23 Furthermore, some authors observed that an increasing CHA 2 DS 2 -VASc was associated to an increased rate of high atrial rate responses in a population without previous diagnosis of AF, and thus with an increased probability of developing atrial arrhythmias. 24 Saliba et al underlined that higher CHA 2 DS 2 -VASc scores were directly associated with new-onset of AF. 25 All these studies suggest a potential role of CHA 2 DS 2 -VASc as a marker of atrial electrical or mechanical remodeling, which could be responsible of AF recurrences after cardioversion. However, its predictive value for recurrences of AF is controversial. [26][27][28][29][30][31][32] Thus, we performed a systematic review and individual patient pooled meta-analysis to assess the value of the CHA 2 DS 2 -VASc score as a predictor of early AF recurrence after successful cardioversion.

| Search strategy
We performed a systematic review and meta-analysis following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) amendment to the Quality of Reporting of Meta-analyses (QUOROM) statement. 33 analyzed the records and decided those deserving a full-text analysis.
The same reviewers (MS, FV) independently analyzed references of all the evaluated articles to include papers not found with the database search strategy. Disagreement was solved with consensus.

| Quality assessment
Two unblinded reviewers (RP, MS) independently evaluated the quality of the included studies using a modified version of the Newcastle-Ottawa Scale (NOS) for cohort studies 37 (Table S1, Supporting Information), excluding the analysis of the section "Comparability" and question 2 of the section "Selection" ("selection of the non-exposed cohort"). Discrepancies between reviewers have been solved by consensus. No study was excluded on the basis of this analysis. The maximum score obtained was 6 Table S1.

| Data analysis and synthesis
Demographics and other baseline characteristics were summarized in terms of mean ± SD if with normal distribution, otherwise as median and interquartile range. Continuous variables were evaluated for normal distribution with Kolmogorov-Smirnov test. Categorical variables were expressed as number and percentage (%). Variables were compared between patients with and without recurrence of AF, using the t test for independent group, the χ 2 test and the Mann-Whitney U test as appropriate, and a P-value of 0.05 was considered to be statistically significant.
Univariate logistic regression was performed to evaluate the relationship between the baseline population characteristics and the primary outcome ( 3 | RESULTS

| Search strategy
A total of 2408 records were analyzed. After the first evaluation of titles and abstracts, 22 studies were screened and of these 15 were excluded with reasons as reported in Figure S1, while the remaining seven were analyzed as full-paper. [26][27][28][29][30][31][32] Thereafter the seven corresponding authors were contacted for joining the patient-level meta-analysis. Three authors agreed to share data and were included in qualitative and quantitative analysis 26-28 ( Figure S1 and Table S1).  Figure 1.

| Primary outcome
Results of the univariate analysis are summarized in independent predictive variables of the recurrence of AF (Table 2).

| DISCUSSION
In addition to the well-established ability to predict thromboembolic risk, our individual patient pooled meta-analysis shows that CHA 2 DS 2 -VASc score predicts also the risk of AF recurrence after electrical or pharmacological cardioversion in a common clinical low thromboembolic risk population (median of CHA 2 DS 2 -VASc score = 2 1-3 ). Furthermore, CHA 2 DS 2 -VASc score, considered both as continuous and dichotomous variable (with a cut-off value of ≥2), has proved to be an independent predictor of early recurrence of AF/atrial flutter after electrical or pharmacological cardioversion. The ROC curve analysis showed that a CHA 2 DS 2 -VASc score ≥2 was linked to a 37% increase in risk of recurrence of arrhythmia. This finding could be related to the ability of the score to indirectly quantify complex pathophysiological substrates and modifiers responsible for AF. Patients with high CHA 2 DS 2 -VASc score are exposed to several factors recognized as perpetrators of the arrhythmia, which induce maladaptive changes at a cellular and extracellular level leading to a more favorable substrate for the permanence and the recurrence of AF despite cardioversions.
We also identified chronic kidney disease (GRF < 60 mL/min) as an important predictor of early recurrence of AF in our population.
Prevalence of AF is usually higher in patients with chronic renal impairment probably because of the increased sympathetic tone and renin-angiotensin-aldosterone system activation which, in turn, cause atrial electrical and structural remodeling. 40 The predictive value of the score for risk of AF recurrence after cardioversion in patients with chronic kidney disease, however, has never been reported before.
PAD also was found to be a predictor of early recurrence of AF. 45 PAD is known to be linked with an increased risk of AF but the mechanisms underlining are not fully understood. 41    The cut-off value of CHA 2 DS 2 -VASc score ≥2 may identify patients at higher risk of AF recurrences after cardioversion, in particular with comorbidities like PAD or CKD. New studies might be necessary to test if the addition of these two variables to the CHADs-VASC could increase the sensitivity and specificity of the score on AF recurrences. Therefore, in patients with a CHA 2 DS 2 -VASc score ≥2, if a rhythm control strategy is opted, it is reasonable to initiate antiarrhythmic prophylaxis after cardioversion. 8,43 Alternatively, a catheter ablation of the arrhythmic substrate could be considered. 43 Finally, also, the setting of the cardioversion has to be analyzed; as a matter of fact our findings are useful in hemodynamically stable patients with AF. In an acute setting with acute instable patients cardioversion cannot be postponed and the trigger of the arrhythmia must be identified and treated.

| Study limitations
This is a meta-analysis and data are obtained retrospectively by each corresponding author; thus, bias related to incomplete data reporting cannot be excluded. Complete information regarding some variables, such as smoking habit, COPD, dyslipidemia, and ECG (eg, signs of atrial enlargement as atrial diameter or area) are lacking. We also had

FIGURE 2
Forrest plot of the relation between CHA2DS2-VASc (as ordinal variable) and atrial fibrillation recurrences. Data are displayed as odds ratio (95% CI). CI, confidence interval FIGURE 3 Forrest plot of the relation between CHA2DS2-VASc ≥2 (as nominal variable) and atrial fibrillation recurrences. Data are displayed as odds ratio (95% CI). CI, confidence interval incomplete data on the use of renin-angiotensin inhibitors and statins, which could have lowered the chance of recurrence of the arrhythmias.
The vast majority of the patients included in the meta-analysis were enrolled in the study of Jaakkola et al 28 Nevertheless, the analysis of I 2 disclosed the absence of heterogeneity (I 2 = 0). The multivariate analysis in each single study was lightly modified, based on the clinical variables available for each single study.

| CONCLUSIONS
The CHA 2 DS 2 -VASc score could be useful to predict early recurrence of AF/atrial flutter in the first 30 days after cardioversion.