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Atrial Fibrillation Following Patent Foramen Ovale Closure

Systematic Review and Meta-Analysis of Observational Studies and Clinical Trials
Originally published 2021;52:1653–1661


    Background and Purpose:

    Multiple studies evaluated whether patent foramen ovale (PFO) closure reduces the risk of ischemic stroke. One commonly reported complication of PFO closure is the development of atrial fibrillation (AF), which is itself a powerful stroke risk factor that requires specific management. This study aims to evaluate the frequency of AF in patients post-percutaneous closure of PFO and the clinical factors that predict AF detection.


    Studies were identified by systematically searching EMBASE and MEDLINE databases on July 11, 2019. Meta-analysis of proportions was performed, assuming a random-effects model.


    A total of 6 randomized controlled trials and 26 observational studies were included, comprising 3737 and 9126 patients, respectively. After PFO closure, the rate of AF development was 3.7 patients per 100 patient-years of follow-up (95% CI, 2.6–4.9). The risk of AF development is concentrated in the first 45 days post-procedure (27.2 patients per 100 patient-years [95% CI, 20.1–34.81], compared with 1.3 patients per 100 patient-years [95% CI, 0.3–2.7]) after 45 days. Meta-regression by age suggested that studies with older patients reported higher rate of AF (P=0.001).

    In medically treated patients, the rate of AF development was 0.1 per 100 patient-years of follow-up (95% CI, 0.0–0.4). Closure of PFO is associated with increased risk of AF compared with medical management (odds ratio, 5.3 [95% CI, 2.5–11.41]; P<0.001).


    AF is more common in PFO patients who had percutaneous closure compared with those who were medically treated. The risk of AF was higher in the first 45 days post-closure and in studies that included patients with increased age.


    Patent foramen ovale (PFO) is present in 20% to 25% of the general population. Case-control studies have shown that PFO is strongly associated with ischemic stroke, especially in younger patients and cryptogenic stroke.1–6 This has led to multiple randomized controlled trials7–11 examining whether percutaneous PFO closure reduces future stroke risk.

    One of the commonly reported complications of PFO closure is the development of atrial fibrillation (AF), which is itself a powerful stroke risk factor that requires specific management. The incidence of AF after PFO closure is mostly reported in the first few weeks after the procedure, but long-term development of AF may also occur. Additionally, undetected paroxysmal AF may have caused the stroke, and the PFO may be an incidental finding given its high frequency in the general population.

    While there has been a recently published meta-analysis12 that specifically studied AF in patients who had PFO closure, it included only randomized controlled trials and was not limited to the ischemic stroke population. Patients with PFO who experienced an ischemic stroke/transient ischemic attack may have a different AF risk profile compared with those who had not. Furthermore, some nonrandomized studies had similar, and sometimes more rigorous, AF follow-up protocols compared with published randomized controlled trials and may offer further insight into this topic.

    The aim of this study was to perform a meta-analysis of the available literature to determine the incidence of AF on longitudinal follow-up of PFO patients, both those who underwent PFO closure and those who were managed medically. Clinical factors that are associated with AF detection will also be explored.


    This systematic review and meta-analysis was registered with PROSPERO (The International Prospective Register of Systematic Reviews; CRD42019109505) and follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline for meta-analysis reporting.

    Search Strategy

    Articles for review were retrieved by searching the databases MEDLINE and EMBASE (inception to January 2018) on July 11, 2019, using the key terms “patent foramen ovale,” “atrial septal defect,” “atrial fibrillation,” “atrial flutter,” “atrial arrhythmias,” “closure,” “transcatheter closure,” “surgical closure,” “ischaemic stroke,” and “cryptogenic stroke” and associated MeSH headings (Table I in the Data Supplement). Title and abstract screen was performed independently by V.N.T. and J.Z.-J.C. using the Rayyan tool.13 Full-text review of the remaining articles was performed by J.Z.-J.C. This strategy was supplemented by a manual search of reference lists from key articles.

    Inclusion and Exclusion Criteria

    We considered all original research, including prospective or retrospective cohort studies, case series, and comparative studies. We included studies that evaluated the rate of AF on longitudinal follow-up of PFO patients, both with and without PFO closure. Studies with <50 patients and those that did not formally evaluate for AF beyond the periprocedural period were excluded. We excluded composite studies that examined both PFO and atrial septal defect closure, unless PFO-specific outcomes were separately reported and the PFO component contained ≥50 patients. We also excluded articles in languages other than English, abstracts, and studies in nonstroke populations. For studies where PFO closure was performed for varied indications, stroke/transient ischemic attack must constitute ≥80% of the cases to be included in the analysis. Publications were evaluated for duplicate or overlapping data, and only the most complete studies were included. Unpublished data were not sought.

    Quality and Bias Assessment

    Assessment for study quality and bias was performed by J.Z.-J.C. and V.N.T. using the SIGN tool.14 Conflict was resolved by discussion and consensus.

    Data Extraction

    Data extraction was performed by J.Z.-J.C. using a standardized Excel worksheet. We collected information on principal author, year of publication, study design, sample size, and methods for AF detection (unspecified, medical records, history/questionnaire, ECG, Holter monitor of at least 24 hours duration, or loop recorder). For the incidence of AF, we collected event counts and calculated patient-years over which follow-up for AF took place (patient number multiplied by the latest time point [in years] where follow-up for AF was performed). We also collected clinical variables known to predispose patients to AF, including average age, proportion of women, and proportion of patients with hypertension and diabetes.

    Statistical Analysis

    For all analyses, we adopted a random-effects model using the method of DerSimonian and Laird. This method assumes that different studies are estimating different but related effect sizes and is a more conservative approach compared with fixed effects model when heterogeneity is present. We calculated the pooled estimate after Freeman-Tukey double arcsine transformation15 to stabilize the variance and calculate score (Wilson)16 CIs.

    For the rate of AF on longitudinal follow-up of patients with PFO, with and without closure, meta-analysis of proportions was performed using Stata metaprop.17 The pooled estimates were expressed as event count/100 patient-years of follow-up. All pooled estimates were presented with their 95% CIs and 2-tailed P. A P of <0.05 was considered statistically significant.

    Heterogeneity of the results was tested using the χ2, I2,18 and τ2 tests. Heterogeneity was considered statistically significant if I2>50% with P<0.10. A cutoff of P<0.10 was used rather than the traditional P<0.05 due to the lower power of these tests in meta-analyses where studies have smaller sample size or are few in number. To identify the sources of heterogeneity across studies, meta-regression was performed to assess the contribution of each prespecified variable (ie, age, proportion of women, proportion of patients with hypertension and diabetes, and methods of AF detection) to the overall heterogeneity.

    An exploratory analysis segregating the rate of AF by time period was performed, using the cutoff of 45 days to delineate early versus late AF. This cutoff was artificial and chosen as it was reported in a previous randomized control trial.9 The incidence of AF in the first 45 days was calculated using this formula: n/(N×45/365), where n refers to AF event counts over this time period and N, number of patients in each study. For the incidence of AF after 45 days, patient-years were calculated as follows: total patient-years of follow-up minus patient-years for the first 45 days of follow-up.

    Publication bias was assessed graphically using the funnel plot and further assessed using Egger regression asymmetry testing.19 The intercept of the linear regression line with the y axis is used to measure asymmetry. If the intercept is significantly different from zero, this suggests the presence of publication bias.


    Study Selection

    The search strategy retrieved 1804 abstracts for review. Of these, 1442 were considered inappropriate following title/abstract screen. The remaining 362 articles were reviewed in full. References of included articles were screened by J.Z.-J.C., and one additional study was identified for inclusion into the final analysis.

    The progress through each step of the review process resulted in a final number of 32 included studies (Figure 1).

    Figure 1.

    Figure 1. Study selection flowchart.

    Bias Analysis

    Overall, studies minimized selection bias by including consecutive patients from the ischemic stroke population. Seven studies20–27 did not explicitly state or had varied methods for excluding AF at baseline. This may have led to some patients being mislabeled as having cryptogenic stroke.

    Attrition bias could not be assessed in many studies, as the completeness of follow-up was not reported.

    Detection bias was an issue for the majority of studies, including all randomized controlled trials, due to the use of only ECG or 24-hour Holter monitoring to follow-up AF. This likely leads to significant underdetection of AF. Symptom-driven investigations on unblinded subjects also introduce another element of detection bias. Lastly, several studies21,23–25,28–31 suffer from confounding bias, as important AF risk factors such as hypertension were not reported.

    Bias analysis for nonrandomized studies is summarized in Table II in the Data Supplement.

    A total of 6 randomized controlled trials7–11,27 and 26 observational studies20–25,28–47 were included, comprising 3737 and 9126 patients, respectively. Full characteristics of the included study are detailed in Table III in the Data Supplement. After PFO closure, the rate of AF development was 3.7 patients per 100 patient-years of follow-up ([95% CI, 2.6–4.9] P<0.001; Figure 2). There is substantial heterogeneity (χ2=606.7, P≤0.001, I2=94.9%). The risk of AF development is concentrated in the first 45 days post-procedure (27.2 patients per 100 patient-years [95% CI, 20.1–34.8], compared with 1.3 patients per 100 patient-years [95% CI, 0.3–2.7]) after 45 days.

    Figure 2.

    Figure 2. Frequency of atrial fibrillation (AF) post-patent foramen ovale closure. ES indicates effect size.

    Meta-regression by proportions of hypertension and diabetes, prevalence of previous cerebrovascular events, and method for AF detection did not detect a significant interaction with the rate of AF. Meta-regression by age and proportion of women showed an association with the risk of AF when tested individually. However, on testing these variables collectively, only age remained statistically significant, with studies with older patients reporting a higher rate of AF (P=0.001; Figure I in the Data Supplement; Table IV in the Data Supplement).

    Seven studies,7–11,27,46 with a total of 1899 patients, reported on the rate of AF on longitudinal follow-up of medically managed PFO patients (Table III in the Data Supplement). The pooled estimate on the rate of AF development was 0.1 per 100 patient-years of follow-up ([95% CI, 0.0–0.4] Figure 3). There is moderate heterogeneity (χ2=15.9, P=0.01, I2=62.2%). Meta-regression by age and method of AF detection showed an association with the risk of AF when these variables were tested individually (Table V in the Data Supplement). This was no longer statistically significant when these variables were combined in a multivariable meta-regression. This observation likely relates to the study by Bonvini et al,46 which was the only study utilizing loop recorder for AF detection and reported a considerably higher rate of AF (7.8 patients per 100 patient-years of monitoring). It also contained patients of a slightly older age (mean, 48 years) compared with the remaining 5 studies (mean, 43.8–46.2 years).

    Figure 3.

    Figure 3. Frequency of atrial fibrillation (AF) on longitudinal follow-up of medically managed patients. ES indicates effect size.

    Six randomized controlled studies7–11,27 directly compared PFO closure with medical therapy (Table III in the Data Supplement). Closure of PFO is associated with increased risk of AF compared with medical management (odds ratio, 5.3 [95% CI, 2.5–11.4]; P<0.001; Figure 4). There is moderate heterogeneity (χ2=6.38, P=0.372, I2=21.6%). Meta-regression by age, proportions of hypertension and diabetes, prevalence of nonindex cerebrovascular event, and method of AF detection did not demonstrate a significant interaction (Table VI in the Data Supplement).

    Figure 4.

    Figure 4. Risk of atrial fibrillation (AF) in patent foramen ovale (PFO) patients treated with PFO closure vs medically. OR indicates odds ratio.

    For all the analyses above, there is no statistical evidence of publication bias on Egger regression asymmetry testing. However, the funnel plot for studies examining the rate of AF in PFO closure patients exhibits significant scatter of studies beyond the triangular region. After segregating the rate of AF post-PFO closure by time periods (AF <45 and >45 days), the scatter is reduced especially for the early time period (Figure 5).

    Figure 5.

    Figure 5. Funnel plots for publication bias in studies reporting rate of atrial fibrillation post-patent foramen ovale closure.A, Rate of atrial fibrillation overall. B, Early atrial fibrillation. C, Late atrial fibrillation.


    This study-level meta-analysis evaluated studies with longer term follow-up and showed that PFO patients with ischemic stroke/transient ischemic attack who were managed medically have a low rate of AF development. In contrast, PFO patients who underwent percutaneous PFO closure have a 5-fold increase in the risk of AF. This risk of AF is concentrated in the first 45 days after PFO closure and may or may not persist.

    Age was found to be a significant interacting factor, with studies containing older patients reporting a higher rate of AF. This is consistent with the well-established, age-dependent risk of AF in the general population. However, the heterogeneity in study results was high even after adjusting for age and other prespecified covariates. This may be due to inherent heterogeneity in study designs, variation in closure devices used, as well as bias resulting from the inclusion of small studies24,31,37,38 that reported considerably higher rates of AF. An exploratory analysis segregating the rate of AF by time period was performed, using the cutoff of 45 days to delineate early versus late AF. This segregation led to a reduction in the degree of heterogeneity and demonstrated that the risk of AF is concentrated in the early postprocedural period. There are several possible mechanisms for this observation. The procedure itself can cause atrial irritation, and the device may trigger an inflammatory response or act as a mechanical barrier, creating a macroreentrant circuit.32,41,42,48 While AF is frequently considered a transient postprocedural phenomenon, the study by Johnson et al49 found that postprocedural ECG changes, such as an increase in P-wave duration and QT interval, persisted on intermediate and longer term follow-up. This suggests that the alteration to cardiac conduction pathways may be more permanent than thought previously. Whether this translates to higher risk of arrhythmias and stroke in the longer term is unclear.

    In our study, the incidence of AF in those managed medically is comparable with published population estimates.50–53 For example, in the Rotterdam study,52 the incidence of AF was estimated at 0.11 patients per 100 patient-years for people aged 55 to 59 years, gradually increasing by age to 2.07 patients per 100 patient-years for those aged 80 to 84 years. However, the incidence of AF in the late post-PFO closure period was higher than that observed in the Rotterdam study. Given that PFO closure reduces recurrent stroke overall, this would tend to argue against a major role of postprocedural AF in long-term stroke risk. Further studies on the persistence, duration, and overall burden of AF using loop recorders are warranted to define the relevance of AF in this situation.

    The long-term antithrombotic management of postprocedural AF remains unclear. Of included studies that reported on the pattern of anticoagulant use, triggers for anticoagulant initiation included recurrence of AF after initial successful cardioversion,29–31,38 AF persisting for >48 hours,29,38 and AF detection beyond the early postprocedural period.30,40 A proportion of patients required short-term (<6 months) anticoagulation treatment only.43 It is likely that many individual patient factors, such as burden of AF, CHA2DS2-VASc score, the presence of left atrial structural abnormalities, and bleeding risk, also contribute to the complex decision-making process.

    There are several limitations to this study. First, all but 3 studies28,39,46 suffered from detection bias (Table II in the Data Supplement), as they utilized routine ECGs, with or without once-off or symptom-triggered 24-hour Holter monitoring for baseline and follow-up AF detection. It is known that AF is often paroxysmal and asymptomatic, and these methods likely lead to underdetection of AF. Purely symptom-driven monitoring strategies additionally bias AF detection rates. This was illustrated by the CRYSTAL AF trial (Cryptogenic Stroke and Underlying AF),54 which reported a much higher rate of AF of 12.4% at 12 months with insertable cardiac monitors. This is in contrast to the rate of 2% in the control group, where a mix of ECG and Holter monitoring was performed at the discretion of the clinician. The 2016 European Society of Cardiology Guidelines for the Management of AF55 recommend that at least 72 hours of continuous cardiac monitoring be performed for patients with ischemic stroke/transient ischemic attack. In the absence of adequate AF monitoring, some of the cryptogenic stroke cases included in these studies may in fact have AF as the underlying cause, and the true long-term incidence of AF in both the closure and medical groups may be higher.

    Second, the clinical relevance of detecting AF at a single time point after closure is unknown, and additional factors such as the duration and burden of AF are probably important in determining stroke risk. AF episodes after closure may be self-limiting and not confer a higher risk of AF in the future. AF episodes in the randomized clinical trials did not seem to confer a higher stroke risk, and trials of PFO closure have shown reduction in stroke risk in general.

    Third, effect variation due to heterogeneity was high between observational studies. While the adoption of a random-effects model helped provide more conservative estimates in this setting, it may not be statistically appropriate to combine them. Lastly, this is a study-level meta-analysis, and the relationships described are observational associations across trials and are prone to bias by both known and unmeasured confounders. For example, we did not study device-specific risk of AF. Some devices may have a higher risk of AF. Examination of individual patient data will help confirm these associations and offer valuable opportunities to study the impact of other important variables, such as PFO morphology and different closure devices, on the rate of AF.


    PFO closure is associated with a higher rate of AF, especially in the early postprocedural period. The risk of AF reduces after this period. However, it does seem to remain elevated compared with the general population. Medically treated PFO patients have a rate of AF similar to the general population. Future research in this area should ensure adequate exclusion of baseline AF by at least 72 hours of cardiac monitoring and utilize a more rigorous AF follow-up protocol to determine the true incidence of AF.

    Nonstandard Abbreviations and Acronyms


    atrial fibrillation


    patent foramen ovale


    We thank Helen Baxter (Clinical Librarian, Austin Health Sciences Library) for her valuable guidance and input into the systematic search of literature.

    Supplemental Materials

    Tables I–VI

    Figure I

    Disclosures Dr Thijs serves on the advisory board and receives consulting and speaker fees from Medtronic, Pfizer/BMS, and Bayer and Boehringer Ingelheim. The other author reports no conflicts.


    This manuscript was sent to Harold P. Adams, Jr, Guest Editor, for review by expert referees, editorial decision, and final disposition.

    The Data Supplement is available with this article at

    For Sources of Funding and Disclosures, see page 1660.

    Presented in part at the International Stroke Conference, Los Angeles, CA, February 19–21, 2020.

    Correspondence to: Vincent N. Thijs, MD, PhD, Austin Hospital, 145 Studley Rd, Heidelberg, Victoria 3084, Australia. Email


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