Patent foramen ovale in cryptogenic stroke: incidental or pathogenic?

Abstract

Background and purpose: Patent foramen ovale (PFO) is significantly associated with cryptogenic stroke (CS). However, even in patients with CS, a PFO can be an incidental finding. We sought to estimate the probability that a PFO in a patient with CS is incidental.

Methods: A systematic search identified 23 case-control studies examining the prevalence of PFO in patients with CS versus control subjects with stroke of known cause. Using simple assumptions and Bayes' theorem, we calculated the probability a PFO is incidental in patients with CS. Random effects meta-analyses estimated the odds ratio (OR) of a PFO in CS versus control subjects in different age populations, with or without atrial septal aneurysms, and were used to summarize across studies the probability that a PFO in CS is incidental.

Results: The summary OR (95% CIs) for PFO in CS versus control subjects was 2.9 (CI, 2.1 to 4.0). The corresponding ORs for young and old patients (< or >or=55 years) were 5.1 (3.3 to 7.8) and 2.0 (>1.0 to 3.7), respectively. The corresponding probabilities that a PFO in patients with CS is incidental were 33% (28% to 39%) in age-inclusive studies, 20% (16% to 25%) in younger patients, and 48% (34% to 66%) in older patients. These probabilities were much lower when an atrial septal aneurysm was present.

Conclusions: In patients with otherwise CS, approximately one third of discovered PFOs are likely to be incidental and hence not benefit from closure. This probability is sensitive to patient characteristics such as age and the presence of an atrial septal aneurysm, suggesting the importance of patient selection in therapeutic decision-making.

Figure 1. Proportion of CS Patients without PFO, with incidental PFO and with pathogenic PFO

This figure shows how the proportion of incidental versus pathogenic PFO in patients with CS can be calculated based on the prevalence of PFO in CS patients and in controls. Case A shows that when the prevalence of PFO in the CS population is 40% and the prevalence of PFO in the control group is 25%, then 50% of PFOs discovered in CS patients would be incidental. This is based on the assumption that CS patients who have strokes from causes unrelated to PFO will have the same PFO prevalence as the control group (in this case 25%). If the PFO prevalence in CS patients were increased slightly to 50% and the PFO prevalence among control patients were decreased, then the rate of incidental PFOs among patients with CS and PFO would decrease to only 25% (Case B).

Figure 2. Probability that a PFO is incidental in patients with CS, based on case-control studies examining the prevalence of PFO in cases with CS versus controls with stroke of determined cause

Individual studies are represented on the left with first author and year of publication, and prevalence of PFO (# PFO/total number of patients) in cases versus controls. Black boxes with sizes corresponding to each study’s weight in the analysis represent the point estimate of the probability that the PFO is incidental with 95% confidence intervals represented with the grey lines (P 95% 23 CI). The diamond in the last row represents the summary estimate of the probability. The dashed black line to the right of the panel represents a probability of 100% that the PFO was incidental (i.e. not related to the CS). Panel A: age-inclusive studies, Panel B: analyses in younger patients, and Panel C: analyses in older patients.

Figure 2. Probability that a PFO is incidental in patients with CS, based on case-control studies examining the prevalence of PFO in cases with CS versus controls with stroke of determined cause

Individual studies are represented on the left with first author and year of publication, and prevalence of PFO (# PFO/total number of patients) in cases versus controls. Black boxes with sizes corresponding to each study’s weight in the analysis represent the point estimate of the probability that the PFO is incidental with 95% confidence intervals represented with the grey lines (P 95% 23 CI). The diamond in the last row represents the summary estimate of the probability. The dashed black line to the right of the panel represents a probability of 100% that the PFO was incidental (i.e. not related to the CS). Panel A: age-inclusive studies, Panel B: analyses in younger patients, and Panel C: analyses in older patients.

Figure 2. Probability that a PFO is incidental in patients with CS, based on case-control studies examining the prevalence of PFO in cases with CS versus controls with stroke of determined cause

Individual studies are represented on the left with first author and year of publication, and prevalence of PFO (# PFO/total number of patients) in cases versus controls. Black boxes with sizes corresponding to each study’s weight in the analysis represent the point estimate of the probability that the PFO is incidental with 95% confidence intervals represented with the grey lines (P 95% 23 CI). The diamond in the last row represents the summary estimate of the probability. The dashed black line to the right of the panel represents a probability of 100% that the PFO was incidental (i.e. not related to the CS). Panel A: age-inclusive studies, Panel B: analyses in younger patients, and Panel C: analyses in older patients.