Is patent foramen ovale a modifiable risk factor for stroke recurrence?

Abstract

Although the prevalence of a patent foramen ovale (PFO) in the general population is ≈25%, it is approximately doubled among cryptogenic stroke (CS) patients. This has generally been attributed to paradoxical embolism, and many physicians recommend PFO closure to prevent recurrence. However, the benefit of PFO closure in patients with stroke has not been demonstrated. Furthermore, the epidemiology of stroke recurrence in patients with CS with PFO versus without PFO and in those with large right-to-left shunts versus small right-to-left shunts has yielded results that appear difficult to reconcile with the hypothesis that paradoxical embolism is an important cause of stroke recurrence. The purpose of this review is to critically examine the epidemiologic evidence that PFO is a potentially modifiable risk factor for stroke recurrence in patients with CS. The evidence suggests that many patients with CS and PFO have strokes that are PFO attributable, but many have strokes that are unrelated to their PFO. We introduce the concept of "PFO propensity," defined as the patient-specific probability of finding a PFO in a patient with CS on the basis of age and other risk factors. We show that this value is directly related to the probability that CS is PFO attributable. Because there is substantial heterogeneity in both PFO propensity and recurrence risk among patients with PFO and CS, stratification for PFO closure by these joint probabilities will likely prove crucial for appropriate patient selection.

Figure 1. Relative Risk of Recurrence in Cryptogenic Stroke with and without PFO

The cumulative risk of recurrent stroke or death stratified by baseline PFO status in the PFO in Cryptogenic Stroke Study. This figure, from Homma et al, is based on data from patients with both cryptogenic strokes and strokes of known cause.

Figure 2. Proportion of Patients with Cryptogenic Stroke and PFO with Incidental 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. As indicated in Figure 2, 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%). Adapted from Alsheikh-Ali AA et al.

Figure 3. PFO Prevalence in Cryptogenic Stroke vs Stroke of Known Cause

This figure shows forest plots of random-effects meta-analyses of case-control studies examining the prevalence of PFO in cases with CS versus controls with stroke of determined cause. Panel A shows the odds ratio of finding a PFO in patients with cryptogenic stroke versus stroke of known cause. Panel B shows the same data after Bayesian transformation to yield the probability that the PFO is incidental. Adapted from reference Alshiekh-Ali et al.

Figure 4. PFO Propensity and the Probability that a Stroke is PFO-attributable

We define PFO propensity as the probability of finding a PFO in a patient, based on patient-specific characteristics (such as age and the presence or absence of hypertension, diabetes and hypercholesterolemia). Through Bayes’ theorem, it is directly (though non-linearly) related to the probability that a cryptogenic stroke is PFO-attributable (in patients with both cryptogenic stroke and PFO).