Predicting risk of AF in ischaemic stroke using sinus rhythm ECG abnormalities: A meta-analysis

Objective: To identify ECG changes in sinus rhythm that may be used to predict subsequent development of new AF. Method: We identified prospective and retrospective cohort or case control studies evaluating ECG patterns from a 12-lead ECG in sinus rhythm taken in hospital or community predicting subsequent development of new AF. For each identified ECG predictor, we then identify absolute event rates and pooled risk ratios (RR) using an aggregate level random effects meta-analysis. Results: We identified 609,496 patients from 22 studies. ECG patterns included P wave terminal force V1 (PTFV1), interatrial block (IAB) and advanced interatrial block (aIAB), abnormal P wave axis (aPWA), PR prolongation and atrial premature complexes (APCs). Pooled risk ratios reached significance for each of these; PTFV1 RR 1.48 (95% CI 1.04–2.10), IAB 2.54 (95% CI 1.64–3.93), aIAB 4.05 (95% CI 2.64–6.22), aPWA 1.89 (95% CI 1.25–2.85), PR prolongation 2.22 (95% CI 1.27–3.87) and APCs 3.71 (95% CI 2.23–6.16). Diabetes reduced the predictive value of PR prolongation. Conclusion: APC and aIAB were most predictive of AF, while IAB, PR prolongation, PTFV1 and aPWA were also significantly associated with development of AF. These support their use in a screening tool to identify at risk cohorts who may benefit from further investigation, or following stroke, with empirical anticoagulation.


Introduction
Embolic stroke of undetermined source (ESUS) is a term developed in 2014 referring to patients who present with non-lacunar embolic strokes where there is no other identifiable cause at presentation. These patients account for at least 25% of all stroke presentations. 1 While it was initially hypothesised that ESUS patients may benefit from anticoagulation, there is currently no evidence to support this treatment over antiplatelets. Two large studies failed to demonstrate benefit with dabigatran or rivaroxaban respectively over aspirin, 2,3 as has preliminary data from a study using apixaban in an enriched cohort. 4 The lower stroke recurrence rate in the dabigatran arm of RESPECT-ESUS 3 was not statistically significant, though in several post-hoc subgroup analyses of this and NAVIGATE-ESUS, 2 superiority of anticoagulation compared with aspirin was statistically significant, [5][6][7] including among patients with LV dysfunction, 5 patients above the age of 75 or with renal impairment. 7 It is therefore plausible that a subgroup of ESUS patients can be identified based on clinical markers, who may benefit from anticoagulation.
Atrial fibrillation (AF) is classically associated with 25% of all strokes, 8,9 though was found to be as high as 36% in one metropolitan study. 10 The lack of clear temporal association between episodes of AF and stroke 11,12 has led to the hypothesis that AF-related stroke may be caused by atrial cardiopathy, and subsequent AF may be a consequence of this already-developing process. While identifying these patients is a priority, current methods are time-consuming, resource intensive and at times invasive. 13 There is therefore an urgent unmet clinical need to find non-invasive and inexpensive biomarkers that can be used to identify patients who are at most benefit from rigorous investigations for AF, or empirical anticoagulation.
Several ECG patterns have been associated with risk of AF. These include atrial premature complexes (APCs) which are markers of atrial cardiopathy, and P wave terminal force V1 (PTFV1), interatrial block (IAB) (subcategorised to advanced IAB and partial IAB), PR prolongation and abnormal P wave axis (aPWA), which reflect an altered atrial conduction pathway. PTFV1 also occurs in the setting of pressure overload. 14, 15 We conducted a systematic review that identified numerous ECG patterns that are predictive of AF. 16 Following on from this, we have conducted a meta-analysis. There have been previous meta-analyses for limited individual ECG abnormalities and risk of AF, however many of these have focussed on populations with significant cardiac comorbidities. We aimed to present a comprehensive and comparative meta-analysis focussing on patients presenting either post-stroke or to primary care.

Search methodology
Our search was conducted on EMBASE and Medline using key search terms consisting of 'electrocardiography', 'atrial fibrillation', 'risk factor', 'predictive value' (see Supplemental Appendix 1 for full search terminology). Further studies were identified from the references of selected articles. We limited our search to articles published in English. Following an initial search, abstracts were screened to determine suitability for inclusion.

Inclusion criteria
We included studies published from January 2014 until September 2022, with the former date chosen due to the development of the term ESUS in that year. 1 We limited the search to prospective, retrospective and case-control cohorts where the exposure of interest included a single 12-lead ECG taken in hospital or community with the primary outcome being incidence of new AF, and where exposure (abnormality 'present' or 'absent') was measured as odds ratio (OR), hazard ratio (HR) or relative risk (RR). We included cohorts presenting following stroke as well as those recruited from primary care or employment health screening.

Exclusion criteria
We excluded studies of known AF or other heart disease. We also excluded studies which relied on exposures other than a 12 lead ECG (e.g. Holter monitor) or where the ECG was studied as a continuous variable. We also excluded study populations taken from a primarily cardiology cohort, as these patients were not felt to be representative of our population of interest and may have cardiac comorbidities that may independently influence our outcome measure.
Our search identified studies assessing multiple ECG patterns for risk of AF, including PTFV1, aIAB, IAB, aPWA, APCs, PR prolongation, P wave amplitude, P wave area, P wave dispersion, QRS prolongation, left ventricular hypertrophy, QRS-T angle, ST-T segment abnormalities and QTc prolongation. We focussed on ECG patterns associated with atrial and AV nodal pathology. An ECG pattern was included for meta-analysis if there were a minimum of two studies with key data. Key data that were screened included study type, ECG pattern and method of measuring this, number of participants, follow-up duration, quantified risk of AF and potential biases. If key data were not available in the paper, the authors were contacted for this information. Where key data remained unavailable, studies were excluded from meta-analysis. Information was collected in accordance with the Guidelines for Meta-analyses and systematic reviews of observational studies for statement and the preferred reporting items for systematic reviews and meta-analyses (PRISMA) for screening studies. The quality criteria included an assessment for bias and all studies had a quality score of good or fair.

Quality assessment and reducing risk of bias
Quality assessment was performed on all studies utilising the Newcastle Ottawa quality assessment scale according to (1) selection of patients, (2) comparability of groups or cohorts and (3) exposure evaluation for case control studies and outcome evaluation for cohort studies. This was performed independently by two investigators (AB and LB).

Data collection process
Data were entered in pre-designed spreadsheets using Microsoft Excel. Abstracts were retrieved as complete manuscripts and assessed against the inclusion criteria. Data extracted included publication details (author, year), study design, follow-up duration, endpoints, quality score, characteristics of the population and sample size. Two reviewers (AB and LB) independently reviewed the data, with disagreements resolved with input from a third reviewer (RS). Principally, information was extracted according to PRISMA guidelines and the PRISMA 2020 checklist was used. Data was then arranged by ECG pattern.

Statistical analysis
We performed separate random effect meta-analyses to derive summary estimates of the pooled risk ratios of AF for each ECG abnormality versus the reference category of 'no ECG abnormality'. We calculated the I 2 statistic to investigate heterogeneity. Funnel plots (Begg and Mazumdar) were generated to investigate publication bias. Finally, where necessary we undertook meta-regression of confounding covariates of biological plausibility or with differences between the studies (average follow up, age, hypertension prevalence, diabetes, heart failure). All analyses were performed using STATA 17.0 (StataCorp LP, TX) and R studio 2022.12.0.

Results
The ECG abnormalities included in this metanalysis were P wave terminal force V1 (PTFV1), partial interatrial block (pIAB), interatrial block (IAB) and advanced interatrial block (aIAB), abnormal P wave axis (aPWA), PR prolongation and atrial premature complexes (APCs). These are defined below. Studies were included if parameters were provided allowing comparison between studies ( Figure 2). Studies measuring APCs either used a 10 s or a 15 s strip.
We identified 46 publications reporting risk of developing AF based on analyses of ECG patterns. We screened the articles to only include a categorical variable (i.e. one that can be included in a risk prediction score) and where sufficient information was reported or available from the authors, yielding 22 separate articles ( Figure 1). The relevant ECG patterns and the number of publications were as follows; P wave terminal force V1 (PTFV1) 5, [17][18][19][20][21] Interatrial block (IAB) 8, 17  The patient and data characteristics of each study are tabulated in Table 1.
Four studies were conducted in post-stroke populations, while 18 studies included community-based cohorts. One study included patients with diabetes. Eighteen studies were in Western (Caucasian) populations and four were from Eastern (Asian) populations. While rates of heart failure were between 3% and 8% in across most populations, there was heterogeneity in hypertension (rates between 13% and 75%) and diabetes (between 6% and 36%) across studies. Median follow up was 11.9 years (IQR 4.9-15). AF incidence was documented using an ECG in 21 studies and using a loop recorder in one study. Diagnosis of AF was made according to ICD criteria in 20 studies. In one study, it was defined as 5 min or longer on ECG monitoring, and in another study, 30 s or longer on implantable loop recorder. 20,33

Interatrial block (IAB) and advanced interatrial block (aIAB)
Nine studies were identified assessing IAB (n = 30,720) and four studies for aIAB (n = 26,834). IAB was defined as pIAB with one or two biphasic P waves in leads II, III and aVF and aIAB was defined as pIAB with biphasic P waves in leads II, III and aVF. Median follow up was 6.6 years for IAB (IQR 2.1-11.9) and 12.5 years for aIAB (IQR 8-15.9). Across the studies, median age was 62 for IAB (54-65) and 57 for aIAB (52-62). 2929 patients with IAB and 2666 with aIAB developed AF during the study; this was a total of 9.5% and 9.9% across the two sets of studies. Among patients with IAB, 15% developed AF compared with 8.9% controls. Among those with aIAB this increased to 34% compared with 9.5% controls. Pooled risk ratios were 2.54 (95% CI 1.64-3.93) and 4.05 (95% CI 2.64-6.22) ( Figure  3). I 2 test for heterogeneity was 86% for IAB and 75% for aIAB. Funnel plots showed Eggers test p value 0.288 for aIAB and 0.003 for IAB.

Abnormal P wave axis (outside 0°-75°)
Seven studies were identified (n = 34,923). Median follow up across studies was 4.9 years (IQR 2-12) and median age was 63 (58-68). Across the studies, 4882 patients Figure 2. ECG abnormalities included in the study: (a) aIAB was defined as P-wave duration >120 ms with biphasic P-waves in leads II, III and aVF, (b) IAB was defined as P-wave duration >120 ms with one or more biphasic P-waves, (c) PTFV1 is the area of the negative deflection of the P-wave in lead V1 × duration of this negative deflection (abnormal >4000 µV × ms), (d) PR prolongation defined as >200 ms, (e) APC and (f) APWA defined as P-wave axis outside 0°-75°.  developed AF during the study period (13%). 25.6% of patients with aPWA developed AF compared to 11.6% in the control group. Pooled risk ratio for development of AF was 1.89 (95% CI 1.25-2.85) (Figure 3). I 2 test for heterogeneity was 97%. Funnel pots showed Eggers test p value 0.01.

Effects of confounders on predicting AF
Meta regression was performed examining the effect of rates of heart failure, hypertension, sex, age, follow-up time and diabetes on the risk of AF for each of the ECG changes.
Only the presence of diabetes attenuated the effect size of PR prolongation on the subsequent risk of AF (p = 0.0183).

Discussion
Our meta-analysis of 22 studies, including 609,496 patients from primary care or post-stroke cohorts, identified six ECG patterns independently associated with risk of subsequent AF. We found the most predictive ECG abnormality for the occurrence of AF was aIAB (RR 4.05, 95% CI 2.64-6.22), followed by presence of at least one atrial premature complex (RR 3.71, 95% CI 2.23-6.16). Presence of IAB, PR prolongation, aPWA or PTFV1 also conferred increased risk of subsequent AF. Our meta-analysis builds on previous studies by improving the statistical power and by providing a comparison of the statistical powers of different ECG abnormalities. Furthermore, we used meta-regression to adjust for confounders. This demonstrated that diabetes reduces the predictive value of PR prolongation, however none of the other demographics had a significant confounder effect. Our findings support previous literature, demonstrating the predictive value of PTFV1, IAB, aIAB and PR prolongation in AF. 14,39,40 However, much of the previous literature included heterogeneous demographics with several studies including patients with significant cardiac comorbidities, which may have influenced the outcome measure. Our findings demonstrate that these ECG abnormalities remain significant predictors of AF when restricted to community-based or post-stroke populations. We also demonstrated that the utility of PR prolongation as a predictor of AF was reduced in the presence of diabetes. This is an interesting result as both PR prolongation and diabetes mellitus are predictors of AF, and diabetes has been recently associated with AV-nodal block, 41 though it may suggest that pathophysiology of AF in diabetes is independent of AV-nodal dysfunction. 42 Further, we add to the previous literature by demonstrating that abnormal P wave axis and APCs on a 12-lead ECG are predictors of AF. While APCs have previously been found to predict AF on a Holter monitor, from previous studies it was not clear that their presence on a 12-lead ECG was a significant predictor. 43 In our study, the presence of at least one APC on an ECG conferred a four-times increased risk of AF.
In contrast to previous studies that have suggested age and hypertension may increase the predictive value of IAB 17,44 we did not demonstrate any other significant effect from age, diabetes, heart failure or hypertension on risk prediction in our study through metaregression.
PTFV1 has previously been recognised as a consistent marker of AF 45 and in a study comparing the predictive value of AF between values, PTFV1 was among the strongest predictors. In our study this association was comparatively weaker and it is possible that a cut-off for abnormal PTFV1 > 5000 µV × ms as has been used in some studies 46 would have a stronger predictive value.
Our study has several strengths, including being the first study to consider multiple ECG abnormalities together in their predictivity of subsequent AF. We did not include studies of poor quality based on the Newcastle-Ottawa scoring system. We included a large sample size from multiple cohorts and different continents, improving its generalisability. We excluded patients recruited from primarily cardiac cohorts, who would have unique characteristics influencing their risk of AF. We also included data on other risk factors that may have influenced the predictive value of the ECG abnormalities in question through meta regression.
Our study has limitations. We included patients recruited from employment health screening or primary care populations, in addition to post stroke populations. This was done as the overall number of studies using post stroke cohorts is small, and it was felt that the data from these cohorts is relevant to a post stroke cohort. This has however introduced heterogeneity to our study, which was reflected in high I 2 numbers across our study. Due to paucity of post-stroke studies, we were unable to compare strength of association between these two populations. Heterogeneity is increased by small variations in diagnosis of AF, with two studies employing prolonged ECG monitoring. Furthermore, diagnosis of AF was through convenience ECG sample in most studies, which likely underestimated the incidence of AF.
We have identified several ECG patterns that can be used to predict AF. APC and aIAB are more predictive than the other ECG patterns studied, followed by IAB, PR prolongation, aPWA and PTFV1. There is a need to identify enriched ESUS cohorts, and biomarkers have been suggested to guide this in clinical use and/or for research purposes. 47 In the setting of a patient presenting following a stroke, with an ECG in sinus rhythm, ECG patterns identified in this meta-analysis could be developed into a computed clinical risk score, combined with clinical factors, to identify one such enriched cohort of ESUS patients who will benefit from intensified cardiac monitoring, or to guide further studies into whether they may benefit from anticoagulation. Negative/neutral ESUS trials create an opportunity to reframe embolic stroke of undetermined source. Rather than assuming that ESUS is undetected AF, future trials could consider ESUS subgroups, with ECG changes high-risk for subsequent AF forming one such subgroup to guide future research. Collaborative prospective observational cohorts investigating the natural history of subsequent stroke could identify the ESUS subgroups where antiplatelet therapy is ineffective to help inform future ESUS trials.