Excessive Supraventricular Ectopic Activity and the Risk of Atrial Fibrillation and Stroke: A Systematic Review and Meta-Analysis

Background: Excessive supraventricular ectopic activity (ESVEA) is correlated with the development of atrial fibrillation (AF) and is frequently observed in ischemic stroke patients. This meta-analysis aims to summarize the evidence on the association between ESVEA and the risk of AF and stroke. Methods: PubMed and Embase databases were systematically searched to identify all publications providing relevant data from inception to 23 August 2022. Hazard ratio (HR) and 95% confidence interval (CI) were pooled using fixed-effect or random-effect models. Results: We included 23,272 participants from 20 studies. Pooled results showed that ESVEA was associated with an increased risk of AF in the general population (HR: 2.57; 95% CI 2.16–3.05), increased risk of AF in ischemic stroke patients (HR: 2.91; 95% CI 1.80–4.69), new-onset ischemic stroke (HR: 1.91; 95% CI 1.30–2.79), and all-cause mortality (HR: 1.41; 95% CI 1.24–1.59). Pooled analysis indicated that ESVEA was not associated with recurrent ischemic stroke/transient ischemic attack (TIA) (HR: 1.24; 95% CI 0.91–1.67). Conclusions: ESVEA is associated with AF, new-onset ischemic stroke, and all-cause mortality.


Introduction
Each year, approximately 795,000 people experience a new or recurrent stroke. Of all strokes, 87% are ischemic strokes [1]. Cryptogenic ischemic strokes (or strokes of unknown cause) are thought to comprise about 25% of all ischemic strokes, and most cryptogenic strokes are thromboembolic [2]. Atrial fibrillation (AF) is the most common cardiac arrhythmia and is an independent risk factor for stroke [3]. Meanwhile, AF is associated with increased in-hospital mortality, not only in ischemic stroke patients [4][5][6][7] but also in patients with cardioembolic stroke [8]. It has also been reported that AF is a predictor of early embolic recurrence in patients with cardioembolic stroke [9] and that early recurrent embolization is the most important predictor of in-hospital mortality [10]. Accumulating studies demonstrated a close relationship between premature atrial contractions (PACs) and AF [11][12][13][14][15][16][17][18][19][20]. Moreover, PACs are common in the general population [21] and patients with ischemic stroke [22]. The term 'excessive supraventricular ectopic activity' (ESVEA), with varying definitions, has been used to describe different manifestations of excessive 2 of 14 atrial ectopic beats in previous studies, which was defined as >30 PACs per hour and/or runs of ≥20 PACs [12,23], PAC/h > 4 and/or supraventricular runs of >5 beats [24], or >100 PACs per 24 h [13,25]. Therefore, ESVEA has been interpreted as a combination of frequent PACs (the number of PACs/h) and/or frequent atrial tachycardia (the number of continuous PACs in any episode). Recently, more observational studies have indicated associations between ESVEA and AF, stroke, and mortality [11,13,15,[26][27][28][29][30].
This meta-analysis aims to summarize the evidence on the associations between ESVEA and AF, stroke, and mortality. Recognizing the risk of stroke after ESVEA is vital for informing early primary and secondary stroke prevention.

Materials and Methods
The meta-analysis was conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [31]. The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO), ID CRD42022353287. As we reviewed only previously published data, local institutional review board or ethics committee approval and subjects informed consent were not required.

Study Search
PubMed and Embase were searched from inception to 23 August 2022 by 2 reviewers (MY and HC). Variations of the following search terms were used: stroke, atrial premature complexes, and atrial fibrillation. The complete search strategy is provided in Supplementary Materials. The reference lists of eligible articles were also scrutinized to find additional data sources.

Study Selection
Two investigators (MY and HC) independently searched the titles and abstracts for articles relevant to our systematic review. If a decision could not be made based on the information in the title and abstract, then the full text was reviewed. Studies were included if they met the following criteria: (1) reported PAC as a risk factor for AF and/or stroke in participants age ≥ 18 years; (2) prospective or retrospective cohort study; (3) follow-up period ≥ 6 months; (4) PAC was detected using ECG or other cardiac telemetry methods, and PAC burden was greater than the presence of PAC; (5) AF and/or stroke were reported as outcome events; (6) the hazard ratio (HR) and the corresponding 95% confidence interval (CI) were reported. The exclusion criteria were as follows: (1) patients with a known history of AF; (2) patients with a history of catheter ablation, percutaneous coronary intervention, or coronary artery bypass graft; (3) patients with implantable cardiac monitoring. There were no language restrictions.

Data Extraction and Quality Assessment
The two investigators independently extracted data from the included studies using prepared forms. The extracted information included the name of the first author, year of publication, country, study design, study population, number of subjects, age, sex, the definition of ESVEA, methods of ESVEA detection, the prevalence of ESVEA, outcomes, and number of interesting outcomes. MY and HC assessed the quality of the included studies according to the Newcastle-Ottawa Scale (NOS) [32]. Any disagreements were resolved by a third author (JY).

Outcomes
The primary outcomes were AF and stroke (including new-onset and recurrent stroke), and the secondary outcome was all-cause mortality.

Statistical Analysis
We pooled the adjusted effect estimates to investigate the independent relationship between ESVEA and the outcomes of AF, stroke, or mortality. The pooled effect estimates were presented as HRs and 95% CIs using the random-effects model (if the heterogeneity was obvious I 2 statistics > 50%); otherwise, the fixed-effects model was adopted. The Egger test was used, and a funnel plot was constructed to evaluate publication bias (p-value < 0.05 was considered significant). Statistical analysis was performed with Stata, version 15.

Results
In total, 2840 records were retrieved through database searching, of which 222 were duplicates. After screening titles and abstracts, 61 articles were included for full-text review. Finally, 20 studies that satisfied all eligibility criteria were included in the review. A detailed flowchart of the screening process is presented in Figure 1.
The primary outcomes were AF and stroke (including new-onset and recurrent stroke), and the secondary outcome was all-cause mortality.

Statistical Analysis
We pooled the adjusted effect estimates to investigate the independent relationship between ESVEA and the outcomes of AF, stroke, or mortality. The pooled effect estimates were presented as HRs and 95% CIs using the random-effects model (if the heterogeneity was obvious I 2 statistics >50%); otherwise, the fixed-effects model was adopted. The Egger test was used, and a funnel plot was constructed to evaluate publication bias (p-value < 0.05 was considered significant). Statistical analysis was performed with Stata, version 15.

Results
In total, 2840 records were retrieved through database searching, of which 222 were duplicates. After screening titles and abstracts, 61 articles were included for full-text review. Finally, 20 studies that satisfied all eligibility criteria were included in the review. A detailed flowchart of the screening process is presented in Figure 1.

Association between ESVEA and AF in the Ischemic Stroke Patients
Five studies assessed the association between ESVEA and the risk of AF in ischemic stroke patients [22,33,36,39,41]. The random-effects pooled adjusted HR was 2.91 (95% CI 1.80-4.69; I 2 = 63.4%, p = 0.012), indicating that ESVEA increased the risk of AF in ischemic stroke patients (Figure 3).

Association between ESVEA and AF in the Ischemic Stroke Patients
Five studies assessed the association between ESVEA and the risk of AF in ischemic stroke patients [22,33,36,39,41]. The random-effects pooled adjusted HR was 2.91 (95% CI 1.80-4.69; I 2 = 63.4%, p = 0.012), indicating that ESVEA increased the risk of AF in ischemic stroke patients (Figure 3).

Discussion
In this systematic review and meta-analysis, we summarized the relationship between ESVEA and AF, stroke, and death. Pooled data showed that ESVEA had more than doubled the risk of AF in the general population from twelve studies and in ischemic stroke patients from five studies. Pooled data based on five studies showed that ESVEA was correlated with a nearly two-fold increase in the risk of new-onset ischemic stroke. Ten studies indicated that ESVEA increases more than doubled the risk of all-cause mortality.

Thoughts on Antithrombotic Therapy of ESVEA
Our results indicated that ESVEA increased the risk of AF and new-onset stroke. According to the guidelines, anticoagulation in patients with AF depends on the CHA2DS2-VASc score [47]. However, the current guidelines do not recommend antiplatelet or anticoagulant therapy in patients with ESVEA. Whether non-stroke patients with ESVEA would benefit from antithrombotic therapy is still unclear. Future trials on the primary prevention of stroke using antiplatelet therapy for patients with ESVEA are warranted. Before these trials are carried out, high-quality studies are urgently needed to verify the relationship between ESVEA and the risk of new-onset stroke. In addition, our analysis indicated that ESVEA did not increase the risk of recurrent ischemic stroke/TIA, which  [12][13][14]22,35,36,39,40,43,45].

Discussion
In this systematic review and meta-analysis, we summarized the relationship between ESVEA and AF, stroke, and death. Pooled data showed that ESVEA had more than doubled the risk of AF in the general population from twelve studies and in ischemic stroke patients from five studies. Pooled data based on five studies showed that ESVEA was correlated with a nearly two-fold increase in the risk of new-onset ischemic stroke. Ten studies indicated that ESVEA increases more than doubled the risk of all-cause mortality.

Thoughts on Antithrombotic Therapy of ESVEA
Our results indicated that ESVEA increased the risk of AF and new-onset stroke. According to the guidelines, anticoagulation in patients with AF depends on the CHA2DS2-VASc score [47]. However, the current guidelines do not recommend antiplatelet or anticoagulant therapy in patients with ESVEA. Whether non-stroke patients with ESVEA would benefit from antithrombotic therapy is still unclear. Future trials on the primary prevention of stroke using antiplatelet therapy for patients with ESVEA are warranted. Before these trials are carried out, high-quality studies are urgently needed to verify the relationship between ESVEA and the risk of new-onset stroke. In addition, our analysis indicated that ESVEA did not increase the risk of recurrent ischemic stroke/TIA, which may be due to the use of antiplatelets in 62% of patients after their first stroke [48]. Thus, antiplatelet therapy may be an effective secondary prevention treatment for stroke patients with ESVEA, and further studies are needed to prove this hypothesis.

Definition of ESVEA
At present, the term 'ESVEA' has various definitions from different studies, mainly because the cut-off value for the word 'excessive' is not clear. For example, Binici et al. [12] had set the cut-off value at the top 10th percentile for both frequency of supraventricular ectopic complexes (SVEC) and length of runs of SVEC, so they defined ESVEA as ≥30 SVEC per hour or any episode of runs of ≥20 SVEC. Weber-Krüger et al. [24] had set the cut-off value at the median of PAC frequency and the longest supraventricular run on 24 h-Holter (SV-run 24 h), so they defined ESVEA as PAC/h >4 and longest SV-run 24 h >5. In the future, larger and more standardized studies are urgently needed to unify the cut-off values and definitions of ESVEA. Thus, we could better diagnose ESVEA among patients, with a view toward early AF or stroke prevention.

Detection Methods of ESVEA
Furthermore, we found that the methods for detecting ESVEA were different in the included studies, including routine ECG, 24 h ECG, 48 h ECG, and polysomnogram-based ECG. The American Heart Association/American Stroke Association guideline for the prevention of stroke recommends that prolonged rhythm monitoring (≈30 days) is reasonable within six months of the index event for ischemic stroke or transient ischemic attack (TIA) patients with no other apparent cause [47]. Some studies have indicated the use of prolonged, continuous ECG monitoring for the detection of undiagnosed AF in stroke/TIA patients [49,50]. We need large sample studies with appropriate ECG monitoring methods and adequate follow-up duration to verify that ESVEA increases the risk of AF and stroke in the future.

Limitations
There are several limitations in the present systematic review and meta-analysis. Firstly, the pooled results were highly heterogeneous; we conducted subgroup and sensitivity analyses to find the source of heterogeneity in these studies. When different ECG durations were analyzed as subgroups, the heterogeneity of pooled outcomes between ESVEA and risk of new-onset and recurrent stroke were significantly reduced ( Figures S3 and S4). Although our results indicated that ESVEA increased the risk of AF in the general population, the Egger's test and funnel plot showed publication bias. Large samples and high-quality studies are needed to confirm the results in the future. Secondly, all included studies were observational, stroke subtypes and the duration of follow-up were variable, the detection method and definition of ESVEA were different, and the influence of confounders could not be fully excluded. Thirdly, we could not include any randomized controlled trials or large prospective studies in our analysis due to the lack of such studies, which could affect the reliability of our results.

Future Research
We advocate further investigation of the underlying mechanisms of ESVEA. For example, Bayés syndrome is associated with a high incidence of atrial tachyarrhythmias, which could be the cause of delayed and retrograde activation of the left atrium [51,52]. Bayés syndrome has also been shown to be a predictor of cardioembolic stroke [53][54][55]. Furthermore, high-quality studies are needed to unify the cut-off points of ESVEA so that we can monitor the occurrence of ESVEA in the clinic. Finally, we must conduct clinical trials of ESVEA interventions for the prevention of atrial fibrillation or stroke.

Conclusions
In conclusion, ESVEA is associated with an increased risk of incident AF, new-onset ischemic stroke, and all-cause mortality. Larger and more rigorous studies are urgently needed in the future to verify the relationship between ESVEA and ischemic stroke.

Supplementary Materials:
The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/jcdd9120461/s1, Figure S1: The funnel plot for estimating the association between ESVEA and the risk of AF in the general population, Figure S2: The funnel plot for estimating the association between ESVEA and the risk of all-cause mortality, Figure S3: Forest plot of the association between ESVEA and new-onset ischemic stroke by subgroups, Figure  S4: Forest plot of the association between ESVEA and recurrent ischemic stroke/transient ischemic attack (TIA) by subgroups; Table S1: Quality assessment for the included studies.