We used a Bayesian approach to estimate the probability that a PFO in a patient with CS is an incidental finding rather than pathogenic in 23 case-control studies and summarized these effects using meta-analytic techniques. Our analysis estimates that approximately one third of PFOs discovered in patients with CS are likely to be incidental and unrelated to the stroke (and somewhat higher when estimates are based on studies using non-stroke controls). This estimate is sensitive to patient age, and is higher in older patients. In addition, the probability that a PFO is incidental is much lower in any age when associated with an ASA.
Given the extensive literature associating PFO with CS, the observation that a substantial proportion of discovered PFOs in patients with CS may be incidental might seem surprising. However, the literature to date has focused only on estimating the strength of the association between a PFO and CS, presenting estimates in the form of an OR, the clinical significance of which can be difficult to interpret. The Bayesian approach adopted in the present analysis goes beyond an estimate of association to address the clinically relevant question of whether the discovered PFO is likely to be etiologically related to the stroke.
The heterogeneity between the studies included in the present analysis is not surprising both because study and diagnostic methods vary, and because numerous factors can potentially affect the degree of association between PFO and CS, and thus the likelihood that a discovered PFO in the setting of CS is incidental. For example, PFO has been found to be more likely to be associated with CS in patients who were younger, did not have hypertension (HTN), hyperlipidemia, diabetes or tobacco use.4, 38
In addition to age and conventional stroke risk factors, morphologic features of a PFO may influence the association between PFO and CS and hence the probability that the PFO is incidental.14, 23, 24, 39
In the present analysis, the presence of a PFO with a concomitant ASA yielded a lower probability of it being an incidental finding. Additionally, multiple studies comparing PFO characteristics of patients with CS versus strokes of known cause have found that larger PFO, greater right-to-left shunt and higher septal wall motion mobility, are more frequent in patients with CS.14, 23, 24, 39
Thus, the likelihood that PFO is pathogenic when found in CS patients is sensitive to multiple patient characteristics. For example, even in patients younger than 55, incidental PFOs would be more likely if patients are near the upper margin of the age category and/or have conventional ischemic stroke risk factors (HTN, high cholesterol, DM, smoking) and/or lower risk morphologic/physiologic PFO features on TEE. Conversely, PFOs may more likely be pathogenic even in patients in the older age range in those who do not have other stroke risk factors but do have high-risk features on TEE.
While patient factors associated with PFOs increase the confidence that paradoxical embolism is the likely mechanism for an individual patient’s stroke, these factors may not be the same as those that predict risk of recurrent paradoxical embolism. Additionally, procedural complications of PFO closure include stroke, e.g. from thrombus formation on the device, and so the risk may increase with the intervention.40
Given the significant number of incidental PFOs that are likely to be present and the relatively low risk of stroke recurrence while on medical therapy in patients with CS and PFO, careful assessment of the risks and benefits of treatment options is essential.3
For interventions where the risks and benefits are finely balanced, it has been demonstrated that multivariate predictive modeling can be useful to identify subgroups in clinical trials likely to benefit or not from the tested therapy.41–43
Using our Bayesian framework, baseline characteristics and PFO morphologic features that predict the presence of a PFO in patients with CS can be used to predict the probability that a discovered PFO is likely to be incidental. Predictive modeling can also be performed separately to estimate the probability of stroke recurrence in patients with PFO and CS.4
For trials testing the efficacy of endovascular closure (RESPECT, PC-Trial), stratifying results by the joint probability that the CS was related to the PFO and the probability the stroke will recur offers the potential for a refined and novel approach to patient selection.44, 45
The present Bayesian approach used to derive the probability of an incidental PFO was informed by estimates obtained from case-control studies of PFO in CS, and relied on two basic assumptions. Therefore, proper interpretation of these findings should take into account the inherent limitations of case-control studies including potential selection bias, presence of unmeasured confounders, and possible differential intensity in the investigation of a PFO in CS cases versus controls. Furthermore, the findings are based on two assumptions, namely that the prevalence of PFO would be similar in patients with CS compared to controls if not for those strokes attributable to PFO, and that CS in patients without a detected PFO is not caused by an undetected PFO. While the first assumption is intuitive, the second may not necessarily be true; though presumably PFOs that go undetected are less likely to be of clinical significance. Despite these caveats, the present analysis offers a novel contribution to our intuitive interpretation of case-control studies, by extending such interpretation from association to a measure of attributable risk.
In conclusion, in patients with otherwise CS, about a third of discovered PFOs are likely to be incidental, and hence endovascular closure is not likely to reduce their recurrent stroke risk. This probability is sensitive to patient characteristics such as age, and morphologic features of a PFO such as the presence of a concurrent ASA.